Clostridium perfringens epsilon toxin induces permanent neuronal degeneration and behavioral changes.

Clostridium perfringens epsilon toxin (ETX), the most potent toxin produced by this bacteria, plays a key role in the pathogenesis of enterotoxaemia in ruminants, causing brain edema and encephalomalacia. Studies of animals suffering from ETX intoxication describe severe neurological disorders that are thought to be the result of vasogenic brain edemas and indirect neuronal toxicity, killing oligodendrocytes but not astrocytes, microglia, or neurons in vitro. In this study, by means of intravenous and intracerebroventricular delivery of sub-lethal concentrations of ETX, the histological and ultrastructural changes of the brain were studied in rats and mice. Histological analysis showed degenerative changes in neurons from the cortex, hippocampus, striatum and hypothalamus. Ultrastructurally, necrotic neurons and apoptotic cells were observed in these same areas, among axons with accumulation of neurofilaments and demyelination as well as synaptic stripping. Lesions observed in the brain after sub-lethal exposure to ETX, result in permanent behavioral changes in animals surviving ETX exposure, as observed individually in several animals and assessed in the Inclined Plane Test and the Wire Hang Test. Pharmacological studies showed that dexamethasone and reserpine but not ketamine or riluzole were able to reduce the brain lesions and the lethality of ETX. Cytotoxicity was not observed upon neuronal primary cultures in vitro. Therefore, we hypothesize that ETX can affect the brain of animals independently of death, producing changes on neurons or glia as the result of complex interactions, independently of ETX-BBB interactions.

Pentosan polysulfate preserves renal microvascular P2X1 receptor reactivity and autoregulatory behavior in DOCA-salt hypertensive rats.

Inflammation contributes to ANG II-associated impairment of renal autoregulation and microvascular P2X1 receptor signaling, but its role in renal autoregulation in mineralocorticoid-induced hypertension is unknown. Autoregulatory behavior was assessed using the blood-perfused juxtamedullary nephron preparation. Hypertension was induced in uninephrectomized control rats (UNx) by subcutaneous implantation of a DOCA pellet plus administration of 1% NaCl in the drinking water (DOCA-salt) for 3 wk. DOCA-salt rats developed hypertension that was unaltered by anti-inflammatory treatment with pentosan polysulfate (DOCA-salt+PPS) but was suppressed with "triple therapy" (hydrochlorothiazide, hydralazine, and reserpine; DOCA-salt+TTx). Baseline arteriolar diameters were similar across all groups. UNx rats exhibited pressure-dependent vasoconstriction with diameters declining to 69 ± 2% of control at 170 mmHg, indicating intact autoregulation. DOCA-salt treatment significantly blunted this pressure-mediated vasoconstriction. Diameters remained between 91 ± 4 and 98 ± 3% of control over 65-170 mmHg, indicating impaired autoregulation. In contrast, pressure-mediated vasoconstriction was preserved in DOCA-salt+PPS and DOCA-salt+TTx rats, reaching 77 ± 7 and 75 ± 3% of control at 170 mmHg, respectively. ATP is required for autoregulation via P2X1 receptor activation. ATP- and ß,γ-methylene ATP (P2X1 receptor agonist)-mediated vasoconstriction were markedly attenuated in DOCA-salt rats compared with UNx (P < 0.05), but significantly improved by PPS or TTx (P < 0.05 vs. DOCA-salt) treatment. Arteriolar responses to adenosine and UTP (P2Y2 receptor agonist) were unaffected by DOCA-salt treatment. PPS and TTx significantly reduced MCP-1 and protein excretion in DOCA-salt rats. These results support the hypothesis that hypertension triggers inflammatory cascades but anti-inflammatory treatment preserves renal autoregulation in DOCA-salt rats, most likely by normalizing renal microvascular reactivity to P2X1 receptor activation.

Alkaloids modulate motility, biofilm formation and antibiotic susceptibility of uropathogenic Escherichia coli.

Alkaloid-containing natural compounds have shown promise in the treatment of microbial infections. However, practical application of many of these compounds is pending a mechanistic understanding of their mode of action. We investigated the effect of two alkaloids, piperine (found in black pepper) and reserpine (found in Indian snakeroot), on the ability of the uropathogenic bacterium Escherichia coli CFT073 to colonize abiotic surfaces. Sub-inhibitory concentrations of both compounds (0.5 to 10 µg/mL) decreased bacterial swarming and swimming motilities and increased biofilm formation. qRT-PCR revealed a decrease in the expression of the flagellar gene (fliC) and motility genes (motA and motB) along with an increased expression of adhesin genes (fimA, papA, uvrY). Interestingly, piperine increased penetration of the antibiotics ciprofloxacin and azithromycin into E. coli CFT073 biofilms and consequently enhanced the ability of these antibiotics to disperse pre-established biofilms. The findings suggest that these alkaloids can potentially affect bacterial colonization by hampering bacterial motility and may aid in the treatment of infection by increasing antibiotic penetration in biofilms.

Common variants in TGFBR2 and miR-518 genes are associated with hypertension in the Chinese population.

BACKGROUND: An animal study reported that TGF-ß1 maturation was linked to the homeostasis of blood pressure and elastogenesis of essential hypertension (EH). Recent advances require further research of TGF-ß1 receptor in EH. METHODS: A case-control study comprised of 2,012 adult hypertension case patients and 2,210 adult control subjects was conducted, and the association with blood pressure was further tested in children. Logistic regression and calculated genetic risk score were used to evaluate the effects of one single nucleotide polymorphism (SNP) and multiple SNPs on EH, respectively. RESULTS: The genetic risk score of 10 SNPs showed a significant association with hypertension; the odds ratio of the upper quartile vs. the lower quartile was 1.282 (P = 4.67 × 10(-3)). rs7256241 in miR-518 was significantly associated with diastolic blood pressure (DBP) change in control subjects (P = 0.002), and this association was also observed in children (P = 0.04). The systolic blood pressure (SBP) and DBP of female patients taking reserpine were higher with the C and G alleles of rs3773661 (P = 0.004) and rs7256241 (P = 0.002), respectively. In patients taking Zhen Ju Jiang Ya tablets, SBP and DBP decreased linearly with rs749794 (P = 0.004 and P = 0.048, respectively). SBP decreased linearly with rs1155705 (P = 0.007) and rs11709624 (P = 0.04), but increased with rs1036096 (P = 0.03) in male patients. In male patients taking Jiang Ya tablets, SBP increased linearly with rs11709624 (P = 0.007), DBP increased linearly with rs1155705 (P = 0.03) whereas decreased with rs7256241 (P = 0.04). CONCLUSIONS: Our results suggest that TGFBR2 and miR-518 harbor variants that increase the risk of EH and affect blood pressure homeostasis as well as efficacy of antihypertensive agents.

Comparative extrapyramidal effects of Rauwolfia vomitoria, chlorpromazine and reserpine in mice.

Most antipsychotics interfere with the dopaminergic system, resulting in extrapyramidal effects. This study compared the extrapyramidal effects of chlorpromazine (Cpz), the herb Rauwolfia vomitoria (RV) and its alkaloid reserpine (Res), used as antipsychotics, in mice. Ninety age-matched male CD-1 strain of mice (25-33 g body weight) were divided into 3 groups, each consisting of 5 subgroups (n = 6). Cpz (0.0, 0.25, 1.0, 2.0 and 4.0 mg/kg, i.p.) was administered 30 min before testing. RV (0.0, 0.25, 1.0, 2.0 and 4.0 mg/kg, i.p.) and Res (0.0, 0.1, 0.4, 0.8, 1.6 mg/kg, i.p.) were administered 24 h before testing. Locomotor behaviour (open field test) and motor coordination (acceleratory rotarod) were assessed. Mice were also observed for 10 min for tremor and vacuous chewing movement (VCM). CPZ and Res dose-dependently decreased locomotor behaviour and impaired motor coordination (p < 0.01). RV also decreased locomotor behaviour (4.0 mg/kg; p < 0.05) but had minimal effect on motor coordination. VCM was lower in the RV group (0.17 ± 0.16/10 min) than the Res (6.8 ± 1.36/10 min) and Cpz groups (7.83 ± 1.95/10 min): F ((4,25)) = 10.703; p < 0.01. The frequency of bouts of tremor was also lower in the RV group (1.17 ± 0.72/10 min) than the Res (21.2 ± 5.63/10 min) and Cpz (7.83 ± 1.59/10 min) groups: F ((4,25)) = 11.012; p < 0.001. The root bark extract of R. vomitoria, therefore, has great potential in the management of psychotic disorders.

Deep brain stimulation of the substantia nigra pars reticulata improves forelimb akinesia in the hemiparkinsonian rat.

Deep brain stimulation (DBS) employing high-frequency stimulation (HFS) is commonly used in the globus pallidus interna (GPi) and the subthalamic nucleus (STN) for treating motor symptoms of patients with Parkinson's disease (PD). Although DBS improves motor function in most PD patients, disease progression and stimulation-induced nonmotor complications limit DBS in these areas. In this study, we assessed whether stimulation of the substantia nigra pars reticulata (SNr) improved motor function. Hemiparkinsonian rats predominantly touched with their unimpaired forepaw >90% of the time in the stepping and limb-use asymmetry tests. After SNr-HFS (150 Hz), rats touched equally with both forepaws, similar to naive and sham-lesioned rats. In vivo, SNr-HFS decreased beta oscillations (12-30 Hz) in the SNr of freely moving hemiparkinsonian rats and decreased SNr neuronal spiking activity from 28 ± 1.9 Hz before stimulation to 0.8 ± 1.9 Hz during DBS in anesthetized animals; also, neuronal spiking activity increased from 7 ± 1.6 to 18 ± 1.6 Hz in the ventromedial portion of the thalamus (VM), the primary SNr efferent. In addition, HFS of the SNr in brain slices from normal and reserpine-treated rat pups resulted in a depolarization block of SNr neuronal activity. We demonstrate improvement of forelimb akinesia with SNr-HFS and suggest that this motor effect may have resulted from the attenuation of SNr neuronal activity, decreased SNr beta oscillations, and increased activity of VM thalamic neurons, suggesting that the SNr may be a plausible DBS target for treating motor symptoms of DBS.

Comparative effects of Rauwolfia vomitoria and chlorpromazine on locomotor behaviour and anxiety in mice.

AIM OF THE STUDY: Since remedies for mental disorders have been sought through both orthodox and traditional medicine this study compared the effects of the antipsychotic, chlorpromazine (Cpz), the herb Rauwolfia vomitoria (RV) and its alkaloid reserpine (Res) in mice. MATERIALS AND METHODS: Ninety male CD-1 strain of mice (75-80 days old; 30-34 g body weight) were divided into 3 major groups and each consisting 5 subgroups (n=6). Cpz (0.0, 0.25, 1.0, 2.0 and 4.0 mg/kg, i.p.), was administered 30 min before testing. RV (0.0, 0.25, 1.0, 2.0 and 4.0 mg/kg, i.p.) and Res (0.0, 0.1, 0.4, 0.8, 1.6 mg/kg, i.p.) were administered 24 h before testing. The open field test was used to assess locomotor and exploratory behaviour, acceleratory rotarod for motor coordination, light/dark box for anxiety. RESULTS: CPZ dose-dependently decreased locomotor and exploration behaviour and impaired motor coordination (p<0.01). RV also decreased locomotor behaviour at 4.0 mg/kg (p<0.5) but did not alter exploration and motor coordination. Res however, decreased locomotion and exploration and impaired motor coordination 0.8 and 1.6 mg/kg (p<0.05). In the light/dark box, CPZ increased anxiety related behaviour at 1.0, 2.0 mg/kg (p<0.05) whereas RV dose-dependently decreased anxiety from 1.0 to 4.0 mg/kg (p<0.01). Res, unlike RV, dose-dependently increased anxiety related behaviour from 0.4 to 1.6 mg/kg. CONCLUSION: Root bark extract from Rauwolfia vomitoria produced better behavioural effects with less distortion in motor coordination when compared to chlorpromazine and so has a great potential as an alternative antipsychotic agent compared to chlorpromazine. Since Res did not produce same effects as RV, the effect of RV may not be due solely to Res as claimed.

Catecholamine-producing cells in the synovial tissue during arthritis: modulation of sympathetic neurotransmitters as new therapeutic target.

BACKGROUND: The proinflammatory and anti-inflammatory role of the sympathetic nervous system in early and late inflammation is an unresolved paradox. A drastic loss of sympathetic nerve fibres in the synovial tissue of patients with rheumatoid arthritis (RA) has previously been demonstrated. The presence of tyrosine hydroxylase (TH)-positive cells in RA and osteoarthritis (OA) has been determined, but the role of these cells in inflammation is still unclear. OBJECTIVE: To characterise TH-positive cells in inflamed RA and OA synovial tissue and to study their role in inflammation. METHODS: Synovial samples were obtained from 32 patients with OA and 19 patients with RA and from 10 control patients. Synovial tissue samples were used for immunofluorescence staining. Synovial cells were isolated by tissue digestion and immediately used for cell culture. For in vivo experiments, collagen type-II arthritis in DBA/1J mice was induced. RESULTS: TH+ cells were present only in inflamed tissue and not in controls. Catecholamine-storing vesicles and vesicular monoamine transporter 2 (VMAT2) were identified in the synovial tissue. Experimental increase of cytoplasmic catecholamines by VMAT2 blockade strongly reduced tumour necrosis factor (TNF) independently of canonical extracellular ß-adrenergic signalling. In addition, VMAT2 blockade increased cyclic AMP (cAMP) and cAMP responsive element binding protein, responsible for TNF inhibition. In vivo, appearance of VMAT2 positive cells was confirmed. VMAT2 blockade ameliorated inflammation also in vivo. CONCLUSIONS: This study demonstrates that local catecholamine-producing cells start to replace sympathetic nerve fibres around the onset of disease, and modulation of locally produced catecholamines has strong anti-inflammatory effects in vivo and in vitro.

[Milestones of cardiovascular therapy. IV. Reserpine]. / Milníky kardiovaskulární terapie. IV. Reserpin.

Reserpine, the purified alkaloid of Rauwolfia serpentina, was the first potent drug widely used in the long-term treatment of hypertension. Rauwolfia serpentina is a tropical woody plant of the Apocyanaceae family ingenious to Asia, South America and Africa. Extracts of its different parts and of plants resembling to rauwolfia were used in Hindu medicine for snakebite, insomnia, insanity and many other diseases and complaints. In Europe, Georg Eberhard Rumpf first reported about rauwolfia in his Herbarium amboinense, 1755. The first modern paper about therapeutic applications of the whole root of rauwolfia was published in 1931 in the Indian Medical Journal by Sen and Bose, and many papers dealing with botanics, chemistry and pharmacology then appeared in Indian and European periodics. In 1949, Vakil published the first report of the antihypertensive effect of rauwolfia in the British Heart Journal. In the Ciba laboratories in Basel, Switzerland, Mueller, Schlittler and Bein analysed various rauwolfia alkaloids and published in 1952 the first complete report about their chemistry and pharmacology. In the same year, reserpine was introduced under the name Serpasil in the treatment of hypertension, tachycardia and thyreotoxicosis. The combination of reserpine, dihydroergocristine and a diuretic is still on the market (Brinerdin, Crystepin). In psychiatry, reserpine was prescribed as a tranqulizing agent until modem synthetic antidepressant and antipsychotic drugs were introduced. The author also briefly summarizes the chemistry, pharmacology and clinical use of reserpine.

El papel de la medicina herbal ayurvédica en el descubrimiento de las propiedades neurolepticas de la reserpina: a propósito de la Rauwolfia serpentina y los orígenes de la era antipsicótica / The role of the ayurvedic herbal medicine in the discovering of neuroleptic properties of reserpine: Rauwolfia serpentina and the origins of antipsychotic era

En el presente trabajo se revisa el papel de la planta Rauwolfia serpentina en el origen de la denominada "era psicofarmacológica". Para ello, se ha sumarizado su empleo en la tradicional medicina ayurvédica, fundamentalmente en los trastornos mentales. En el clásico tratado hindú Charaka Samhita ya se hablaba de una forma de psicosis denominada Ounmaad, uno de cuyos remedios terapéuticos era la "planta de raíz de serpiente". La medicina científica se ocupó del estudio, durante la primera mitad del siglo XX, de las actividades farmacológicas de esta planta, destacando las propiedades sedantes e hipotensivas. Finalmente, se analiza el proceso de aislamiento de los alcaloides de la raíz de Rauwolfia, iniciado en la India, y que concluyó con el descubrimiento de la reserpina en los laboratorios suizos de Ciba. Con la reserpina, el arsenal farmacológico para el tratamiento de la esquizofrenia, sustentado únicamente en la clorpromazina, se vio sustancialmente implementado; permitiendo un gran avance en el manejo de los trastornos psiquiátricos (AU)

Activity of anticancer compounds against Trypanosoma cruzi-infected mice.

Chagas' disease, which is caused by Trypanosoma cruzi, remains essentially incurable. Due principally to a lack of profit incentive, the pharmaceutical industry has had limited interest in developing new antichagasic drugs. Thus, a search for agents that exhibit activity against T. cruzi, although medicaments have been developed for the treatment of other diseases, seems justifiable. Responding to evidence that the principal biochemical differences between mammalian cells and African trypanosomes apply equally to T. cruzi, our evaluations were conducted. Previous work showed the effectiveness of anticancer agents against T. rhodesiense. In the present studies, 76 anticancer compounds were assessed for their ability to suppress the trypomastigotes of T. cruzi- infected mice. Five compounds were found to be active. The most effective was cycloheximide, which was more than six times as effective as the standard, nifurtimox.

A randomised crossover comparison of reserpine and sustained-release nifedipine in hypertension.

OBJECTIVE: To compare the effectiveness of the combination of hydrochlorothiazide (HCT) plus sustained-release nifedipine with the combination of HCT plus reserpine in lowering high blood pressure (BP) unresponsive to HCT monotherapy. DESIGN: An open, randomised crossover drug trial. SETTING: Outpatients' clinic in Parirenyatwa Hospital, Harare, a tertiary referral centre. SUBJECTS: 32 Black patients of both sexes with newly diagnosed or previously treated hypertension aged between 21 and 65 years who had a BP > 140/95 after receiving HCT 25 mg daily for four weeks were studied. INTERVENTION: Patients were kept on HCT 25 mg daily and were randomised to receive either reserpine 0.25 mg daily or nifedipine (Adalat Retard) 20 mg bd for four weeks. This was followed by a two week washout period during which patients received HCT 25 mg daily only. After the washout period patients were crossed over to the alternative treatment for four weeks. Patients were kept on HCT 25 mg daily throughout the trial. MAIN OUTCOME MEASURES: The main outcome measure was the fall in BP which was taken as the difference between the BP at baseline and the BP at the end of each treatment period. Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements were taken. RESULTS: Both second line drugs were effective in lowering SBP and DBP and there was no significant difference between them. Nifedipine reduced SBP by 18.9 mmHg (95% CI 12.1 to 25.7) and DBP by 9.6 mmHg (95% CI 7.2 to 12.0). Reserpine reduced SBP by 15.9 mmHg (95% CI 8.4 to 23.4) and DBP by 11.1 mmHg (95% CI 7.5 to 14.6). However, only two patients attained the target DBP of < or = 90 mmHg after each active treatment period. CONCLUSION AND RECOMMENDATIONS: Since both agents were equally effective in reducing both SBP and DBP and reserpine is much cheaper than nifedipine, it is recommended that for a developing country like Zimbabwe, the combination of HCT and reserpine at the above doses should be used as the first step to treat mild to moderate hypertension without evidence of end organ damage. However, further trials should compare BP lowering effects as well as end organ protection offered by the trial drugs.

[Chronosensitivity to adelphane-esidrex and sinepres and effectiveness of treatment of patients with hypertension]. / Khronochuvstvitel'nost' k adel'fanu-ézidreksu i sinepresu i éffektivnost' lecheniia bol'nykh gipertonicheskoi bolezn'iu.

24-h trends in central and peripheral circulation in response to pharmacological tests were registered in 40 patients with stage II essential hypertension (EH). Rhythmic patterns of hemodynamic parameters (heart rate, systolic pressure, stroke volume, etc.) sensitivity to adelphane-esidrex were found. Hypotensive effect of this drug was maximal in morning hours because of the fall in arterial pressure due to reduced peripheral resistance. Sinepres chronotherapy given to 18 EH patients turned out superior to conventional treatment (1 pill 3 times a day) given to 20 EH patients. When taken into consideration, chronosensitivity to the above drugs may bring about a reduction in daily and course doses and earlier occurrence of a hypotensive effect.

Diabetic nephropathy: a comprehensive approach.

By the time the traditional dipstick test shows excess urinary albumin, glomerular damage may be beyond repair and nephrotic syndrome virtually guaranteed. More sensitive assays provide earlier warning, allowing the clinician to institute a surveillance and antihypertensive program that--along with dietary glycemic control--can stave off disease progression.

Abnormal electrocardiograms and cardiovascular risk: role of silent myocardial ischemia. Evidence from MRFIT.

The Multiple Risk Factor Intervention Trial (MRFIT) was designed as a primary prevention study to test the effect of multifactorial intervention on long-term outcome in men with a combination of risk factors that placed them in the top 10-15 percentiles of risk for coronary artery disease. Of the 12,866 patients in this study, the 3,600 men (about 28%) with abnormalities in the baseline electrocardiogram were prospectively identified. They were expected to be at increased risk for coronary events compared with those without electrocardiographic abnormalities. Analysis of cumulative mortality data following antihypertensive regimens that included high dosages of diuretics revealed an association between electrocardiographic abnormalities at rest and diuretic treatment that related to adverse outcome. When the dosages of the diuretic were lowered, this trend was reversed. It is proposed that diuretic-related hypokalemia may predispose patients who may have silent myocardial ischemia to potentially fatal arrhythmias and that use of potassium-sparing antihypertensive regimens be considered in high-risk hypertensive patients.

[Effect of the treatment on hemodynamic indicators and plasma testosterone level in patients with juvenile hypertension]. / Vliianie lecheniia na pokazateli gemodinamiki i kontsentratsiiu Testosterona v plazme krovi u bol'nykh iovenil'noi gipertenziei.

The effect of anapriline, corinfar and reserpine on parameters of hemodynamics and plasma testosterone was evaluated in 60 juvenile hypertension patients who achieved pronounced hypotensive response. It was established that the level of sex hormones tended to diminution by the end of the treatment month 1 or 2, this drop being more noticeable in reserpine administration. Basing on this evidence it would be beneficial for patients suffering from juvenile hypertension in need of chemotherapy to take courses of the above drugs.

Inhibitory effects of chlorogenic acid, reserpine, polyprenoic acid (E-5166), or coffee on hepatocarcinogenesis in rats and hamsters.

Four different experiments were performed in order to examine the modifying effects of chlorogenic acid (CA), reserpine, polyprenoic acid (E-5166), and coffee on chemical carcinogenesis in rats or hamsters. Experiment 1: The numbers of hyperplastic liver cell foci and the incidence of colon tumors in male and female Syrian golden hamsters given a single intravenous injection of methylazoxymethanol (MAM) acetate and then fed the diet containing 0.025% CA for 24 wk were significantly lower than those of hamsters given MAM acetate alone. Experiment 2: The incidence of altered hepatocellular foci in female ACI/N rats given N-2-fluorenylacetamide (FAA, 0.02% in diet) for 10 wk and reserpine (weekly subcutaneous injections, 1 microgram/g body weight) during or after (17 wk) FAA exposure was significantly lower than that of rats given FAA alone. Experiment 3: The number of hepatocellular foci in male ACI/N rats given 0.02% FAA diet for 13 wk and E-5166 by gavage (40 mg/kg body weight, 3 times/wk) for 16 wk after the end of FAA exposure was significantly smaller than that in rats given FAA diet alone. Experiment 4: Incidences of liver tumors and hepatocellular foci of rats given concurrent dietary administration of aminopyrine (0.01%) and sodium nitrite (0.1%) and coffee solution as a drinking water for 630 da were significantly lower than those of rats given aminopyrine and sodium nitrite. Thus, the tested compounds had inhibitory effects on chemical carcinogenesis in liver or colon.

Effect of reserpine on salivary gland radioiodine uptake in thyroid cancer.

Nine patients with thyroid cancer were treated with reserpine in an attempt to reduce radiation exposure to the salivary glands from 100-150 mCi doses of I-131 therapy to thyroid remnants or metastases. Three control patients were not treated with reserpine but did receive 100-150 mCi of I-131. Parotid/background ratios of activity after radioablative doses of I-131 in patients not treated with reserpine were significantly higher than the patients treated with reserpine, and this was also true seven days after the radioablative dose. Combined therapy with reserpine, chewing gum, lemon candies, and hydration is suggested for the prevention of sialadenitis and xerostomia due to large doses of radioiodine.

Antihypertensive drug therapy prevents cerebral microvascular abnormalities in hypertensive rats.

Studies were performed on anesthetized 16-18 week old normotensive Wistar-Kyoto rats, spontaneously hypertensive rats, and Goldblatt two-kidney one clip renal hypertensive rats, treated from age 4-5 weeks with an oral antihypertensive regimen consisting of hydralazine, reserpine, and chlorothiazide. Measurements of flow and intravascular pressure in the cerebral microvasculature were made via a constantly suffused open cranial window using video microscopy. A significant upward shift was seen in the pressure range for cerebral blood flow autoregulation in both groups of untreated hypertensive animals. Following treatment, the autoregulatory range in both hypertensive models was restored to a level nearly identical to control. The prevention of this shift in treated animals was due primarily to the prevention of structural microvascular adaptations that occur in untreated hypertensive animals. By preventing elevations in microvascular pressure, treatment may have eliminated the major stimulus for development of hypertrophy in resistance vessels. However, a persistent increment of arteriolar wall mass in treated spontaneously hypertensive rats may represent a hyperplastic response not influenced by treatment. Likewise, a persistent constriction of the smallest arterioles in treated renal hypertensive rats may represent a differential sensitivity of microvessels to circulating vasoactive agents. It appears that treatment initiated in the prehypertensive state, or before significant sustained hypertension has occurred, can markedly reduce the cerebrovascular morbidity associated with two different forms of hypertension.