Untreated Spontaneously Hypertensive Research Articles

Preventing Hypertension After Ischemic Stroke In The Spontaneously Hypertensive Rat

Over 80% of patients show a transient increase in blood pressure (BP) after ischemic stroke, regardless of their previous blood pressure level. However, whether this increased pressure is necessary to enhance or maintain oxygenation of penumbra tissues remains uncertain. We aimed to determine the impact of treating post‐stroke hypertension in the spontaneously hypertensive (SH) rat model of ischemic stroke.Male SH rats (374±9 g) were instrumented to allow the long‐term recording of BP, intracranial pressure (ICP) and brain tissue oxygen in the penumbra (pO2) via telemetry. After recording a 3‐day baseline on Day 0 an ischemic stroke was induced via a two‐hour occlusion of the middle cerebral artery (MCAo). BP was either Untreated (n= 6) or Treated (n=6) and controlled to baseline levels with the clinically‐indicated adrenergic antagonist, labetalol (0.25 mg/kg/hr sc via osmotic pump). Behavioural testing and neurological scoring (SHIRPA score) were performed on Days 1, 3, 7 and 10 to evaluate the functional recovery from stroke over time, and postmortem stroke infarct size assessed by histology on Day 10.Following a stroke, BP increased rapidly in Untreated SH rats, reaching a peak of 35±3 mmHg above baseline within 24 hours. Treatment with labetalol significantly reduced BP on D0 and D1 (p<0.05), which in combination with a small increase in ICP (3±0.8 mmHg in Untreated; 0.4±0.3 mmHg in Treated; p=0.047) on D0 resulted in a lower cerebral perfusion pressure (CPP=MAP‐ICP) in Treated animals. Penumbra tissue oxygen levels were not reduced with labetalol treatment, with a small but significant elevation in pO2 seen in the treated animals in the 24 hours after stroke. Treated and Untreated rats showed a similar impairment after stroke in terms of neurological score, functional outcome and infarct volume (274±26 mm3 vs Untreated 256±11 mm3).Treating post‐stroke hypertension does not appear to have a major impact on the functional recovery from stroke in rats with pre‐existing hypertension. Future studies will examine the impact of blood pressure lowering in rats already receiving treatment for pre‐existing hypertension, and of treatment to normotensive BP levels in SH rats to mimic the clinical situation of ‘undiagnosed pre‐existing hypertension’.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Amlodipine and atorvastatin improve ventricular hypertrophy and diastolic function via inhibiting TNF-α, IL-1β and NF-κB inflammatory cytokine networks in elderly spontaneously hypertensive rats

This study aimed to examine the effects of amlodipine and atorvastatin alone or in combination on the regulation of inflammatory cytokines and the underlying mechanisms in elderly spontaneously hypertensive (SH) rats. The level of serum hs-CRP was detected with ELISA. The serum TNF-α and IL-1β levels were assessed by radioimmunity assay (RIA). Cardiac inflammatory cell infiltration was observed by HE staining. The protein levels of TNF-α, IL-1β, of NF-κB P65 and IκBα were detected by immunoblotting. The intracellular localization of NF-κB p65 was observed using immunohistochemistry. Amlodipine or atorvastatin obviously ameliorated the myocardial inflammatory cell infiltration in SH rats, which was further improved by combinatorial treatment with amlodipine and atorvastatin. Either amlodipine or atorvastatin decreased plasma IL-1β content in SH rats, but there was no significant difference when compared with untreated SH rats. However, the combination of amlodipine and atorvastatin significantly decreased plasma IL-1β level in SH rats. Moreover, amlodipine or atorvastatin intervention significantly reduced myocardial TNF-α and IL-1β protein levels in SH rats, which was further suppressed by the combination of amlodipine and atorvastatin. In addition, amlodipine or atorvastatin inhibited the activity of NF-κB signaling in SH rats, which was further suppressed by combinatorial treatment. Furthermore, amlodipine or atorvastatin restored the activity of IκB-α in SH rats, which was enhanced by combinatorial treatment. Our results demonstrated amlodipine and atorvastatin improved ventricular hypertrophy and diastolic function possibly through the intervention of TNF-α, IL-1β, NF-κB/IκB inflammatory cytokine network. Our study suggests that amlodipine combined with atorvastatin may have additive effect on inhibiting inflammatory response.

Assessment of cardiac autonomic tone in conscious rats.

Cardiac autonomic tone can be assessed either by estimating separately vagal and sympathetic tones or by evaluating the net effect of their interaction, the so-called sympathovagal balance (SVB). To compare the most commonly used methods in rats, telemetric recordings of the electrocardiogram were performed in normotensive WKY rats, and in groups of spontaneously hypertensive (SHR) rats that were either untreated or chronically treated with the cholinesterase inhibitor, pyridostigmine, to enhance vagal tone. Cardiac autonomic blockers were administered alone and in combination, so that heart rate (HR) could be measured (1) under resting conditions, (2) with either autonomic branch blocked, and (3) with both branches blocked (which provided intrinsic HR, iHR). SVB was assessed as the ratio of resting HR to iHR. This calculation pointed to a sympathetic predominance in untreated SHRs and even more so in WKY rats, and to a marked vagal predominance in pyridostigmine-treated SHRs. By contrast, the ratio between low and high frequency components (LF/HF) of RR interval spectra did not significantly differ between the groups. Each autonomic tone was quantified as the HR change induced by its selective blocker or as the difference between iHR and HR after blockade of its counterpart. Both pharmacological methods indicated vagal enhancement in treated SHRs, but provided opposite results in terms of vagal vs. sympathetic predominance. These data seriously question the use of the LF/HF ratio as an index of SVB, and the possibility to reliably estimate vagal and sympathetic tones separately through current pharmacological approaches in conscious rats.

Angiotension II receptor 1 blocker modifies the expression of apoptosis‐related proteins and transforming growth factor‐β1 in prostate tissue of spontaneously hypertensive rats

To assess whether angiotensin II (Ang II), important in hypertension and highly expressed in benign prostatic hyperplasia (BPH), is involved in prostate growth, by analysing changes in the histological composition, tissue apoptotic status and level of transforming growth factor-beta1 (TGFbeta1) induced by an Ang II type 1 receptor blocker, losartan, in the prostates of spontaneously hypertensive (SH) rats. We assessed four groups of six rats each: normotensive Wistar-Kyoto counterparts of SH rats; untreated SH rats; SH rats given low-dose losartan (10 mg/kg/day for 10 weeks); and SH given high-dose losartan (30 mg/kg/day for 10 weeks). We evaluated the histological composition and expression of TGFbeta1 and apoptosis-related proteins, i.e. Bax and the 116-kDa poly (adenosine diphosphate-ribose) polymerase (PARP), by Western blotting in the rat prostate ventral lobes. Compared with Wistar-Kyoto rats, untreated SH rats had a significantly increased epithelium component in the prostate (P < 0.01), but with losartan treatment, SH rats showed less of the epithelium component than untreated rats (P < 0.01 for both low- and high-dose losartan). Western-blot analysis showed a significantly increased level of Bax in high-dose losartan-treated rats (P < 0.01). The expression of 116 kDa PARP was also decreased in these rats (P < 0.01), which suggests increased caspase-3 activity. In addition, TGFbeta1 levels were significantly elevated in high-dose losartan-treated rats (P < 0.01). These results show that losartan can induce apoptosis of prostate epithelium and increase the TGFbeta1 expression in SH rats, suggesting that Ang II stimulation might be involved in the pathogenesis of BPH, which might correlate with the regulation of TGFbeta1 expression.

Simvastatin improves endothelial function in spontaneously hypertensive rats through a superoxide dismutase mediated antioxidant effect

Hydroxymethylglutaryl coenzyme A (HMGCoA) reductase inhibitors have beneficial effects beyond their cholesterol-lowering properties. The antioxidant mechanism of HMGCoA reductase inhibitors is not completely understood. To elucidate the antioxidant effect of simvastatin. We studied the influence of simvastatin treatment on the development of hypertension, modification of antioxidant systems, and reactivity of aortic rings in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Simvastatin had no effect on blood pressure (BP). Simvastatin treatment (either 1 or 2 mg/kg body weight for 12 or 20 weeks) increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in SHR rats compared with untreated control SHR rats. Carbachol-induced relaxation of aortic rings was impaired in control SHR rats and was restored by simvastatin treatment. Addition of SOD improved the response in control SHR rats and did not have any effect in treated SHR rats. Addition of diethyldithiocarbamic acid, a selective inhibitor of SOD, produced a mild non-significant impairment in carbachol-induced relaxation in control SHR rats, suggesting a deficient antioxidant system in these animals. However, in treated SHR and in WKY rats, impairment of the relaxation was marked, implying that SOD activity in these animals was important to maintain endothelial function. In aortic rings without endothelium from SHR rats, contraction induced by free radicals was substantially higher than in WKY rats. This effect was attenuated in 1-mg-treated rats and abolished in 2-mg-treated rats. Simvastatin promotes intracellular antioxidant systems, fundamentally SOD, restoring endothelial function but not having any effect on blood pressure.

Predisposition of spontaneously hypertensive rats to develop renal injury during nitric oxide synthase inhibition

Chronic nitric oxide (NO) synthase (NOS) inhibition results in renal injury. Hypertension is an important risk factor for renal injury. We studied the influence of preexistent hypertension on the sensitivity for renal injury induced by chronic NOS inhibition in rats. Spontaneously hypertensive (SHR) and normotensive Wistar–Kyoto (WKY) rats were treated with 3, 10, 30 and 100 mg/l Nω-nitro-l-arginine (l-NNA) until death. Systolic blood pressure and proteinuria were measured regularly and compared with time-control measurements in untreated SHR and WKY. In WKY, 3 and 10 mg/l l-NNA did not affect systolic blood pressure, while 30 and 100 mg/l l-NNA resulted in an increase in systolic blood pressure after 12 and 4 weeks, respectively. In contrast in SHR, every dose of l-NNA resulted in an increase in systolic blood pressure after 2 weeks. In WKY, 3 and 10 mg/l l-NNA did not affect proteinuria or survival, while 30 and 100 mg/l l-NNA resulted in an increase in proteinuria after 30 and 9 weeks, and a median survival of 36 and 12 weeks, respectively. In SHR, 3, 10, 30 and 100 mg/l l-NNA resulted in an increase in proteinuria after 30, 12, 3 and 3 weeks, and a median survival of 41, 20, 5 and 3 weeks, respectively. Thus, at every dose of the inhibitor, chronic NOS inhibition resulted in far earlier increases in systolic blood pressure and proteinuria and a marked increase in mortality in SHR as compared to WKY. Indeed, a very low dosage of l-NNA that caused no harm in WKY was followed by marked increases in proteinuria and blood pressure and decreased survival in SHR. Hypertension strongly increases the vulnerability to cardiovascular risk factors that compromise the NO-system.

Antihypertensive drug therapy and antioxidant enzyme mRNA levels in spontaneously hypertensive (SHR) rats

Previous studies have shown that chronic treatment of SHR (spontaneously hypertensive) rats with the antihypertensive drugs captopril, hydralazine and terazosin results in changes in the specific activities of the antioxidant enzymes glutathione peroxidase, catalase and Cu/Zn superoxide dismutase in liver and myocardium. In order to determine if these changes were caused by alterations in the levels of the mRNAs for these enzymes, the tissue levels of the antioxidant enzyme mRNAs have been measured. In myocardium, all three drug treatments increased Cu/Zn superoxide dismutase mRNA but decreased glutathione peroxidase mRNA levels, and in liver, all three drugs changed glutathione peroxidase mRNA levels. In comparison to untreated SHR animals, the levels of all three mRNAs were altered in the myocardium, but not in the liver, of normotensive WKY rats. Comparisons of mRNA levels with tissue enzyme specific activities suggest that tissue antioxidant enzyme expression is, in most cases, regulated by antihypertensive drugs through transcriptional control mechanisms.

Effects of chronic arterial hypertension on constitutive and induced ICAM-1 expression in the splanchnic organ

• Effects of chronic arterial hypertension on constitutive and induced ICAM-1 expression in the splanchnic organs. S Komatsu, J Pan6s, MA Perry#, JM Russell, DN Granger Dept. Physiology, LSU Medical Center, Shreveport, LA 71130 #University of South Wales, Sydney, Australia Recent reports indicate that the endothelial cell adhesion molecule, ICAM-1 is upregnlated in response to endotoxin to a greater extent in cultured endothelial cells derived from spontaneously hypertensive (SHR) than cells norrnotensive (WKY) rats. it remains unknown whether such a difference occurs in vivo and whether vessels in splancbnic organs exhibit these altered responses in Chronically hypertensive animals. The objectives of this study were to characterize and compare the in vivo expression of ICAM-1 in SHR and WKY rats, under basal conditions and after exposure to endotoxin. Methods: ICAM-1 expression was studied in the splanchnic organs of untreated or eadotoxin-treated SHR and WKY rats at 5 hours after endotoxin administration (5mg/kg i.p.). ICAM-1 expression was measured using a25I labeled anti-rat ICAM-1 mAb (1A29), and an isotype matched control mAb: J3~I P-23 (anti-dog ICAM-1) to correct for nonspecific accumulation of the binding mAb. ICAM-1 corrected activity is expressed as (% injected activity ~25I-1A29./g) (% injected activity 13~I-P-23 Ig), Results: Constitutive expression of ICAM-1 was detected in all splanchnic organs. The levels of constitutive expression of ICAM-1 were similar in SHR and WKY. After endotoxin administration ICAM-1 expression significantly increased in all organs except the liver and spleen in both SHR and WKY rats. However, the magnitude of upregu!ation of ICAM1 in both the small and the large intestine was significantly lower in SHR than in WKY (small intestine 0.425-+0.020 vs. 0.527-+0.024 %/g, p<0.01; large intestine 0.317_+0.017 vs. 0.423+0.018 %/g, p<0.01, respectively ). No significant differences hi endotoxin-induced ICAM-1 apregulation were noted between the two groups for fiver, spleen, pancreas~ mesentery, and stomach. Conclusions: Chronic arterial hypertension does not affect constitutive expression of ICAM-1 in splanchnic organs, but is associated with a decreased endotoxin-induced upregnlation of the endothelial cell adhesion molecule in the small and large intestine.(Supported by DK43785) DISCRIMI ANT EFFECTS OF HEMORRHAGIC SHOCK ON PHAGOCYTIC CLEARANCE AND PHAGOCYTIC KILLING BY THE HEPATIC RETICULOENDOTHELIAL SYSTEM ~ , Dajie Wang, ToshJhiko Ma~am~ Andrew Klein and Gregory Bulkley. Dept of Surgery, the Johns Hopkins University, Baltimore, MD

Glomerular dynamics and morphology of aged spontaneously hypertensive rats. Effects of angiotensin-converting enzyme inhibition.

Relationships between glomerular dynamics and renal injury, micropuncture and histological studies were assessed in 73 week-old normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats divided into untreated and angiotension-converting enzyme inhibitor-treated (quinapril; 3 mg/kg/day; for 3 weeks) groups. Urinary protein excretion (UPE) and histologic arteriolar (AIS) and glomerular (GIS) injury scores were determined. Mean arterial pressure (MAP) of untreated SHR was increased compared with WKY (200 +/- 6 vs 119 +/- 4 mm Hg; P < 0.01), effective renal plasma flow (ERPF) was reduced (1.47 +/- 0.21 vs 3.06 +/- 0.26 ml/min/per g; P > 0.01), and filtration fraction (FF) and total renal vascular resistance (RVR) of SHR were increased (P < 0.01). Single-nephron plasma flow (SNPF) of untreated SHR was decreased (174 +/- 17 vs 80 +/- 9 ml/min; P < 0.01), and single-nephron filtration fraction and afferent arteriolar resistance (RA) were increased (19.4 +/- 1.8 vs 30.0 +/- 2.5% and 1.90 +/- 0.25 vs 9.05 +/- 1.35 U, respectively; both P < 0.01). Despite reduced SNPF, glomerular capillary pressure (PG) increased (49.7 +/- 0.7 vs 53.8 +/- 1.3 mm Hg; P < 0.05), the result of efferent arteriolar constriction (1.15 +/- 0.18 vs 2.84 +/- 0.36 U; P < 0.01). Untreated SHR had higher UPE (13.9 +/- 1.5 vs 42.8 +/- 3.2; mg/100 g per day; P < 0.01) and GIS and AIS scores than WKY (4.3 +/- 1.1 vs 64.3 +/- 8.4 and 16.6 +/- 3.1 vs 96.3 +/- 14.4; both P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Bis(maltolato)oxovanadium(IV) attenuates hyperinsulinemia and hypertension in spontaneously hypertensive rats.

We previously reported that bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium complex, decreased plasma insulin concentrations in nondiabetic rats without affecting plasma glucose levels (McNeill JH, Yuen VG, Hoveyda HR, Orvig C: Bis(maltolato)oxovanadium(IV) is a potent insulin mimic. J Med Chem 35:1489-1491, 1992). In this study, chronic oral BMOV treatment was started in 6-week-old spontaneously hypertensive (SH) rats and their Wistar-Kyoto (WKY) controls, and the effects of the drug on insulin sensitivity, plasma insulin, and blood pressure (BP) were studied. BMOV (0.35-0.45 mmol.kg-1.day-1) caused a sustained reduction in plasma insulin (198 +/- 6 vs. untreated 366 +/- 13.2 pM, P < 0.0001) and systolic BP (149 +/- 3 vs. untreated 184 +/- 3 mmHg, P < 0.0001) in SH rats. No changes were seen in WKY rats (plasma insulin: treated 228 +/- 4.8 vs. untreated 222.6 +/- 3.6 pM, P > 0.05; BP: treated 134 +/- 3 vs. untreated 134 +/- 5 mmHg, P > 0.05). At 13 weeks of age, euglycemic clamps were performed in fasted, conscious, mobile rats. During low-dose insulin infusions (14 pmol.kg-1.min-1) with concomitant somatostatin administration, neither hepatic glucose output nor total body glucose uptake differed between the untreated SH and WKY rats. Insulin sensitivity, expressed as steady-state glucose clearance per unit of plasma insulin, was higher in the untreated SH compared with the untreated WKY rats (2.1 +/- 0.2 vs. 1.2 +/- 0.1 ml.kg-1.h-1.pM-1, P < 0.002). BMOV further enhanced insulin sensitivity in SH rats (3.6 +/- 0.4, P < 0.002 vs. untreated SH rats).(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamics and aneurysm development in vascular allografts

Purpose: Mechanical and immunologic factors may play a role in the development of native arterial and biologic graft aneurysms. We developed an experimental rat aortic allograft aneurysm model in which segments of infrarenal aorta were transplanted between hypertensive and normotensive rats to study these factors in this model.Methods: Aortic allografts and autografts were inserted into spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. Effects of immunologic and antihypertensive therapy were evaluated. Graft diameters were followed up with magnetic resonance imaging and at harvest. Direct-pressure measurements were taken and dp/dtmax (force of ventricular contractions) was calculated before harvest.Results: Autografts remained isodiametric and maintained their histologic architecture. Aneurysmal dilation of transplanted segments occurred in SHR host allografts but not in WKY host allografts. Histologic examination of all allograft specimens noted a rejection reaction characterized by inflammatory cell infiltration and medial smooth muscle cell loss. Antigenic enhancement accelerated aneurysm development in SHR hosts but had no significant effect on WKY hosts. Rates of allograft enlargement and final allograft diameters were similar in antihypertensive treated and untreated SHR hosts. The dp/dtmax in untreated SHR hosts was greatest and differed significantly from that in the WKY rats but only marginally from that in treated SHR hosts.Conclusions: Immunologic rejection but not abnormal hemodynamics is necessary for development of allograft aneurysm in this model.

Effects of triiodothyronine in spontaneously hypertensive rats. Studies on cardiac metabolism, function, and heart weight.

We have studied the effects of triiodothyronine (T3) on heart function, on the myocardial oxidative pentose phosphate pathway, and on heart weight in spontaneously hypertensive (SHR) rats. Another aim was to examine whether these T3-effects may be reversible. T3 was administered daily (0.2 mg/kg s.c.) for 14 days. Compared to the untreated SHR controls, T3 induced an increase in heart rate (beats/min) from 357 +/- 10 (n = 17) to 553 +/- 10 (n = 17), in the pressure-rate-product (mm Hg/min) from 78 400 +/- 4500 (n = 15) to 113 700 +/- 4800 (n = 15), and in the heart weight/body weight ratio (mg/g) from 4.2 +/- 0.2 (n = 20) to 5.8 +/- 0.2 (n = 19). The activity of myocardial glucose-6-phosphate dehydrogenase, the first and rate-limiting enzyme of the oxidative pentose phosphate pathway (units/g protein), was elevated from 4.2 +/- 0.2 (n = 9) to 7.0 +/- 0.6 (n = 9) after 14 days of T3-treatment, while the activity of 6-phosphogluconate dehydrogenase, one of the following enzymes in the pathway, was not altered appreciably. These changes returned to the respective control values when T3-treatment was discontinued for 14 days. Our results demonstrate that T3 had a positive chronotropic effect and induced an additional heart enlargement in an animal model with already established cardiac hyperfunction and hypertrophy. The effects on heart function and weight, which were fully reversible, were not as pronounced as in normal Sprague-Dawley rats.

Effects of antihypertensive drugs on heart and resistance vessels

STUDY OBJECTIVE - The aim of the study was to examine the effects of antihypertensive drugs on heart and resistance vessels to see whether regression of peripheral vascular hypertrophy accompanies reduction in cardiac mass. DESIGN - Matched groups of spontaneously hypertensive and control rats were treated for 12 weeks with captopril (average dose 65 mg.kg-1.d-1) or hydrochlorothiazide (73 mg.kg-1.d-1) and compared to untreated groups. Perfusion pressure, which has been validated as an index of hypertrophy of resistance vessels, was determined in hind limbs of pithed rats at constant blood flow and maximum vasodilatation. SUBJECTS - Experimental animals were 14 week old male spontaneously hypertensive (SHR) rats (n = 41) and strictly age matched Wistar Kyoto rats (n = 12). SHR rats were assigned at random to three groups: (a) captopril treated (n = 15), (b) hydrochlorothiazide treated (n = 15), (c) control (n = 11). MEASUREMENTS and RESULTS - Mean perfusion pressure was 29.5(SEM 0.4) mm Hg in untreated Wistar Kyoto rats and 37.4(0.5) mm Hg in untreated SHR rats. In comparison with untreated SHR rats, treatment with captopril lowered blood pressure, perfusion pressure [35.2(0.3) v 37.4(0.5) mm Hg, p less than 0.01)], and left ventricular to body weight ratio [2.28(0.03) v 2.63(0.05) mg.g-1, p less than 0.01)]. Treatment with hydrochlorothiazide also lowered blood pressure but had no significant effect on left ventricular weight to body weight ratio [2.54(0.04)]. However, perfusion pressure was reduced to 35.3(0.5) mm Hg, p less than 0.01. CONCLUSIONS - For equal regression of vascular hypertrophy, captopril and hydrochlorothiazide had different effects on regression of left ventricular hypertrophy. Thus left ventricular and vascular structural changes may respond differently to the same drug in the same animal.

The adenylate cyclase activity in heart membranes from normotensive and spontaneously hypertensive rats, after chemical sympathectomy, suggests the presence of presynaptic secretin receptors

Normotensive (WKY) and spontaneously hypertensive (SHR) male adult rats were sacrified 2 and 3 weeks after 6-hydroxydopamine treatment. Untreated WKY and SHR rats served as controls. In rat heart membranes from WKY rats, 6-hydroxydopamine treatment increased guanosine 5′-O-(2–3-imido)-triphosphate (Gpp(NH)p)-, NaF-, D,L-isoproterenol- and glucagon-stimulated adenylate cyclase activities by 18–38% while secretin stimulation was unaffected. In heart membranes from SHR rats, Gpp(NH)p, NaF, D,L-isoproterenol, or glucagon stimulation of the enzyme was similarly increased by 14–38% whilst the low secretin responsiveness which is characteristic of these animals decreased even further (by 24–47%). These results are consistent with: (1) an up regulation of postsynaptic β-adrenergic receptors coupled to adenylate cyclase after degeneration of adrenergic nerves, and (2) a differential response of secretin receptors coupled to adenylate cyclase in the two strains of rats: there was no change in WKY rats and a decreased response in SHR rats. The possible presence and contribution of presynaptic secretin cardiac receptors is considered.

Arterial muscle membrane abnormalities of hydralazine-treated spontaneously hypertensive rats

Alkaline phosphatase activity and Ca 2+ accumulation were examined in the plasma membrane enriched fractions isolated from mesenteric arteries of spontaneously hypertensive (SHR) and Kyoto-Wistar normotensive (WKY) rats after a long-term antihypertensive treatment with hydralazine. The membrane biochemical abnormalities of arterial smooth muscle such as enhanced alkaline phosphatase activity and reduced ATP-dependent Ca 2+ transport previously observed in untreated SHR were persistently observed in hydralazine treated SHR with normalized systolic blood pressure. Our results suggest that the antihypertensive effects of hydralazine do not involve the reversal or modification of the altered Ca 2+ handling by vascular muscle membrane in hypertension.

Chronic propranolol treatment decreases cardiac β-adrenoceptors in spontaneously hypertensive rats

Spontaneously hypertensive (SHR) rats were treated for 6 months with 41.6 or 94.6 mg/kg per day of (±)-propranolol. Compared to untreated SHR rats, the heart rate and blood pressure in both treated groups were decreased. The cardiac β-adrenoceptor concentration was similar in the untreated and low dose (±)-propanolol-treated group but was decreased by 30% after treatment with the high (±)-propranolol dose. The results suggest that high dose (±)-propranolol treatment reduces the cardiac β-adrenoceptor concentration.

Comparative effects of α-methyldopa, propranolol and hydralazine therapy on cardiac adenylate cyclase activity in normal and spontaneously hypertensive rats

Normotensive (WKY) and spontaneously hypertensive (SHR) male rats were treated orally, one week after weaning for 9 weeks, with α-methyldopa (100 mg/kg per day), propranolol (30 mg/kg per day) or hydralazine (10 mg/kg per day). Untreated WKY and SHR rats served as controls. The development of hypertension in SHR rats was attenuated by treatment but none of the drugs was able to restore the impairment in isoproterenol, secretin and glucagon responsiveness of cardiac adenylate cyclase activity which is characteristic of these animals. In heart membranes from both WKY and SHR rats, α-methydopa treatment increased the number of β-adrenoceptors by 20–32% and the maximal response of adenylate cyclase activity to isoproterenol and glucagon by 20–34%. By contrast, the β-blocker propranolol was ineffective on these parameters. The results obtained are consistent with the hypothesis that the change in adenylate cyclase seen in SHR rats is generic in origin and is not a consequence of hypertension.

Evidence that the Increased Calcium Sensitivity of Resistance Vessels in Spontaneously Hypertensive Rats is an Intrinsic Defect of Their Vascular Smooth Muscle

We have investigated media thickness and noradrenaline- and calcium-sensitivity of isolated mesenteric resistance vessels from spontaneously hypertensive (SHR) and control Wistar-Kyoto (WKY) rats, which had been treated in various ways. Vessels from untreated SHRs had an increased media thickness and increased noradrenaline- and calcium-sensitivity. Anti-hypertensive treatment of SHRs and WKYs with Felodipine reduced blood pressure, eliminated the difference in vessel media thickness, but did not reduce vessel noradrenaline- or calcium-sensitivity. Chemical sympathectomy of SHRs and WKYs at birth likewise resulted in reduced blood pressure, but did not eliminate the difference in vessel media thickness although again vessel noradrenaline- and calcium-sensitivity remained unchanged. Induction of renal hypertension in WKYs caused an increase in blood pressure and increase in vessel media thickness, but did not affect vessel noradrenaline-sensitivity. The results suggest that while vessel media thickness is influenced by blood pressure, the sensitivity differences of SHR resistance vessels are an intrinsic defect of their vascular smooth muscle, independent both of blood pressure and neurogenic influences.

Effect of peripheral sympathectomy on left ventricular ultrastructure in young spontaneously hypertensive rats

Administration of nerve growth factor antiserum (NGFAS) to spontaneously hypertensive (SH) rats during the first week of life prevents or ameliorates the development of hypertension but does not prevent development of left ventricular hypertrophy or dysfunction. Morphometric analysis of electron micrographs prepared from subepicardial myocardial cells of animals sacrificed at age 82 days shows that NGFAS treatment significantly reduces the fall in cellular concentration of mitochondria characteristic of untreated SH controls. In both groups myofibrillar concentrations were identical and correspond to literature values for normotensive rats. The results, which are consistent with independent control mechanisms for growth of mitochondria and myofibrils, suggest that in this model (a) NGFAS affects mitochondrial concentration either via its effect on arterial blood pressure and/or via some other, unidentified mechanism, and (b) the decreased mitochondrial concentration in myocardial cells of untreated SH rats need not be causally related to the observed cardiac dysfunction.

Systemic and regional flow distribution in normotensive and spontaneously hypertensive young rats subjected to lifetime beta-adrenergic receptor blockade.

To determine quantitatively organ blood flow distribution as the result of lifelong beta-adrenergic receptor blockade, 23 and 24 normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats, respectively, were treated from conception with tap water (control; 10 WKY and 8 SHR), propranolol (0.5 mg/ml drinking water; 6 WKY and 8 SHR), or timolol (0.5 mg/ml drinking water; 7 WKY and 8 SHR) via placental circulation, mothers' milk, and drinking water. At 12 weeks of age all six groups were studied hemodynamically under ether anesthesia using an electromagnetic flowmeter and radioactive carbonized (15 micrometer) microspheres. Untreated SHR demonstrated normal cardiac output (CO) and CO distribution to all organs except for myocardium and testes, thereby confirming our previous work. With either propranolol or timolol treatment the course of development and maintenance of arterial pressure was no different than the pure-tap-water-fed WKY and SHR despite an approximate 30% reduction in CO. Further, with both beta-receptor antagonists CO distribution was significantly reduced to skeletal muscle (p less than 0.001), unchanged to the heart, and increased (p less than 0.05) to the remaining organs (including kidneys and brain) in both groups. Thus, as a result of lifelong beta-adrenergic receptor blockade, CO was reduced; and this was associated with a redistribution of blood flow so that flow to the kidney, brain, and splanchnic organs could be maintained at the expense of skeletal muslce perfusion.