Further Decrease In Blood Pressure Research Articles

Інтенсифікація антигіпертензивної терапії у хворих із неконтрольованою артеріальною гіпертензією та надлишковою масою тіла/ожирінням за даними українського дослідження SATISFACTION

Мета дослідження – визначити профіль пацієнтів із артеріальною гіпертензією (АГ) і надлишковою масою тіла (індекс маси тіла (ІМТ) 25–29,9 кг/м2) або ожирінням (ІМТ ≥ 30 кг/м2), які не досягають офісного артеріального тиску (АТ) < 140/90 мм рт. ст. при застосуванні терапії антигіпертензивними препаратами.Матеріали і методи. До багатоцентрового відкритого обсерваційного епідеміологічного дослідження 185 лікарями загальної практики/терапевтами послідовно на прийомі залучено 1798 хворих з АГ, офісним АТ > 140/90 мм рт. ст. та надлишковою масою тіла/ожирінням. Проведено опитування за стандартним опитувальником, загальноклінічне обстеження, виміряно ІМТ, окружність талії (ОТ), надані рекомендації щодо фізичної активності та харчування, здійснена корекція антигіпертензивної терапії на розсуд лікаря. На другому візиті через 1 міс проведено кон­троль АТ, оцінено ефективність призначеної терапії, зміни маси тіла, ІМТ та ОТ, прихильність до терапії. Третій візит, ще через 1 міс, відбувався в телефонному режимі.Результати та обговорення. Середній вік хворих становив (59,06±11,38) року, жінок було 1203 (66,9 %). Надлишкову масу тіла відзначено у 33,4 % випадків, ожиріння – у 66,6 % випадків. Середня маса тіла становила (92,06±14,03) кг, ІМТ – (32,38±4,55) кг/м2, ОТ у чоловіків – (104,92±12,74) см, у жінок – (99,32±12,74) см, тобто домінував абдомінальний тип ожиріння. Сімейний анамнез серцево-судинних захворювань відзначено у 60,7 % осіб, при цьому ніколи не курили 63,6 %. Цукровий діабет або порушення толерантності до глюкози зафіксовано у 11,06 %. Рівень систолічного АТ (САТ) становив (163,15±12,21) мм рт. ст., діастолічного (ДАТ) – (95,62±7,78) мм рт. ст., частота скорочень серця (ЧСС) – (78,16±8,98) за 1 хв, тобто спостерігалася переважно тяжка АГ. На момент залучення в дослідження один антигіпертензивний препарат приймали 38,4 % хворих, два – 47,8 %, три та більше – 13,8 % (переважно модулятори ренін-ангіотензин-альдостеронової системи в комбінації з антагоністами кальцію та гідрохлоротіазидом, більше половини – у формі окремих препаратів). Початкова прихильність до лікування (кількість позитивних відповідей) становила 3,33 бала та була низькою у 73,9 % хворих і тільки у 4,0 % – високою. Лікарями на першому візиті було змінено антигіпертензивну терапію: 84,43 % пацієнтів було рекомендовано оригінальну фіксовану комбінацію периндоприлу й індапаміду в дозуванні 10/2,5 мг; 14,07 % пацієнтів – у дозуванні 5/1,25 мг; 0,95 % пацієнтів – у дозуванні 2,5/0,625 мг; 0,56 % пацієнтів призначено іншу антигіпертензивну терапію. Через 1 міс лікування САТ знизився на (27,12±13,7) мм рт. ст., ДАТ – на (13,32±9,08) мм рт. ст., ЧСС – на (5,2±8,16) за 1 хв (усі р<0,001), що привело до контролю АГ у 74,9 % осіб та поліпшення прихильності до лікування (р<0,05). Подальше лікування впродовж місяця привело до подальшого зниження АТ. Середній САТ через 2 міс становив (130,29±11,58) мм рт. ст., ДАТ – (79,37±6,69) мм рт. ст., знизившись від початкового рівня на (32,87±12,21) та (16,26±8,93) мм рт. ст. відповідно (р<0,0001). Усі зміни АТ мали дозозалежний характер (доза оригінальної фіксованої комбінації периндоприлу й індапаміду) і були максимальними при застосуванні комбінації з дозуванням 10/2,5 мг. Від характеру попереднього лікування, віку обстежених ефективність лікування та прихильність не залежали. Контролю АТ було досягнуто у 93,09 % пацієнтів, прихильність до лікування поліпшилася у 71 %.Висновки. Терапія оригінальною фіксованою комбінацією периндоприлу й індапаміду переважно в максимальних дозах (10/2,5 мг) у попередньо лікованих хворих з АГ і надлишковою масою тіла/ожирінням є ефективною, дозволяє досягти контролю АТ упродовж 2 міс терапії у 93 % хворих незалежно від віку, а також значно поліпшити прихильність до терапії.

Hemodynamic changes in patients with influenza A after propacetamol infusion in the emergency department

ObjectivesRecently, there has been an emerging clinical data suggesting that intravenous propacetamol may cause iatrogenic hypotension. The primary objective of this study was to evaluate hemodynamic changes after propacetamol infusion in the emergency department (ED) with the patients of influenza A. Secondary objective was to assess the incidence of propacetamol-induced significant hypotension and to evaluate factors associated with this adverse effect by comparing two groups of patients with or without a significant reduction in blood pressure (BP). MethodsWe retrospectively reviewed the medical records of the patients with laboratory-confirmed influenza A who received intravenous propacetamol for the control of fever in the ED during the 2015–16 influenza season. Results101 patients of influenza A were included in this study. Overall, all the vital signs including BP, pulse rate and body temperature recorded after propacetamol administration were lower than the pre-infusion values. A significant reduction in BP was observed in 30 (29.7%) patients and 6 (20%) of them required crystalloid infusion. Interestingly, pre-infusion BPs were higher in the group of propacetamol-induced significant hypotension, yet there was no difference in post-infusion BPs between the groups. DiscussionTo our knowledge this is the first study on the effect of intravenous propacetamol in the ED patients with influenza A infection. We hypothesized that the group with a significant reduction in BP could have higher sympathetic tone, consequently showing higher pre-infusion BPs and pulse rate. And there was no difference in post-infusion BPs because baroreflex homeostasis could compensate further decrease in BPs.

Antihypertensive Actions of Moderate Hyperbilirubinemia: Role of Superoxide Inhibition

Moderate (approximately 2-fold) increases in plasma unconjugated bilirubin levels are able to attenuate the development of angiotensin II (Ang II)-dependent hypertension. To determine the specific role of decreases in superoxide production to the blood pressure-lowering effects of moderate hyperbilirubinemia (MHyB), we performed this study, in which the Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin was given to Ang II-infused mice in the presence and absence of moderate hyperbilirubinemia. Apocynin (14mM) was administered in the drinking water prior to treatment with UDP-glucuronosyltransferase 1A1 antisense morpholino (16 μg/kg), which was administered by intravenous injection every third day. Treatments were started before the implantation of Ang II-containing minipumps (1μg/kg/min) and continued throughout the protocol. Ang II infusion increased blood pressure to 145±2mm Hg. Apocynin treatment alone reduced blood pressure to 135±5mm Hg, whereas MHyB alone decreased blood pressure to 118±5mm Hg in Ang II-infused mice. Prior inhibition of NADPH oxidase with apocynin did not result in a further decrease in blood pressure in MHyB mice, which averaged 117±3mm Hg (n = 6 mice per group). In aortic preparations, apocynin treatment decreased Ang II-mediated superoxide production from 2433±120 relative light units (RLU)/min/mg to 1851±126 RLU/min/mg (n = 4 mice per group), which was similar to levels observed in MHyB mice alone (1473±132 RLU/min/mg) or in combination with apocynin (1503±115 RLU/min/mg). Our results indicate that MHyB lowers blood pressure by a mechanism that is partially dependent on the inhibition of superoxide production.

Antihypertensive Actions of Moderate Hyperbilirubinemia: Role of Superoxide Inhibition

Our lab has previously demonstrated that moderate (~ 2 fold) increases in plasma unconjugated bilirubin levels are able to attenuate the development of Angiotensin II (Ang II) dependent hypertension. In order to determine the specific role of decreases in superoxide production to the blood pressure lowering affects of moderate hyperbilirubinemia (MHyB), we performed the current study in which the NADPH oxidase inhibitor, apocynin, was given to Ang II infused mice in the presence and absence of moderate hyperbilirubinemia. Apocynin (14 mM) was administered in the drinking water prior to treatment with UGT1A1 antisense morpholino (ASM; 16 μg/kg) which was administered via intravenous injection every third day. Treatments were started before the implantation of Ang II containing minipumps (1μg/kg/min) and continued throughout the 7 day protocol. Ang II infusion increased blood pressure to 145 ± 2 mmHg. Apocynin treatment alone reduced blood pressure to 135 ± 5 while MHyB alone decreased blood pressure to 118 ± 5 in Ang II infused mice. Prior inhibition of NADPH oxidase with apocynin did not result in a further decrease in blood pressure in MHyB mice which averaged 117 ± 3 (n=6/group). In aortic preparations, apocynin treatment decreased Ang II mediated superoxide production from 2433 ± 120 to 1851 ± 126 RLU/min/mg (n=4/group) which was similar to levels observed in MHyB mice alone 1473 ± 132 or in combination with apocynin 1503 ± 115. Our results indicate that MHyB lowers blood pressure via a mechanism that is independent of the inhibition of superoxide production; however, we cannot exclude the possibility that other antioxidant properties of bilirubin may be important to the antihypertensive actions in Ang II dependent hypertension. This work was supported by grants from the National Heart, Lung and Blood Institute, HL088421 and PO1HL‐51971.

No further decrease in blood pressure when the interval between readings exceeds one hour

The assessment of blood pressure (BP) in individuals is traditionally based on a few BP readings obtained at intervals of just a few minutes. We examined if increasing intervals between BP readings on one visit would have an impact on the BP estimates. We conducted an examination survey of cardiovascular risk factors in the general population aged 25-64 years in Seychelles (Indian Ocean), attended by 1255 of 1565 eligible participants. BP was measured once shortly after participants' arrival to the study centers (BP1) and twice before discharge, 15-351 min later (BP2, BP3; separated by 2 min). Mean (standard error) BP1 was 135.1 (0.7)/87.9 (0.4) mmHg, BP2: 130.7 (0.6)/85.1 (0.4) mmHg and BP3: 128.4 (0.6)/83.9 (0.3) mmHg. The difference in BP between the first and the last measurements (DeltaBP1-BP3) was, respectively, 5.8 (1.3)/2.6 (0.9) mmHg for a time interval between BP1 and BP3 of 15-60 min, 6.3 (0.5)/3.9 (0.3) mmHg for 61-120 min, 6.9 (0.6)/4.1 (0.4) mmHg for 121-240 min and 7.4 (0.7)/4.3 (0.5) mmHg for 241-351 min (P-trend for systolic/diastolic BP: 0.15/0.49). In multivariate analysis, both systolic and diastolic DeltaBP were associated with the initial BP level and the female sex but not with time (in minutes) between BP readings (for systolic/diastolic BP, P=0.12/0.34). The decrease in subsequent BP readings obtained did not differ whether the time interval between BP measurements was larger or smaller than 1 h. This indirectly suggests that extending the time interval between repeated BP readings on one single visit is unlikely to be a valid, alternative strategy to the recommendation of gathering BP readings on several, separate visits to define hypertension.

Is Renoprotection by Angiotensin Receptor Blocker Dependent on Blood Pressure?: The Saitama Medical School, Albuminuria Reduction in Diabetics with Valsartan (STAR) Study

To explore the effects of various antihypertensive regimes on microalbuminuria, an angiotensin II receptor blocker (ARB), valsartan, was substituted for or added to treatment with a calcium channel blocker (CCB). After a 6-month CCB baseline period, 28 Japanese hypertensive patients with incipient diabetic nephropathy (defined as a urinary albumin excretion [UAE] of 30-300 mg/g creatinine), were assigned to two groups according to their blood pressure (BP) levels: in patients with a BP of more than 130/85 mmHg (n=17), valsartan was added to the CCB (Group A), while in patients with a BP <130/85 mmHg, valsartan alone was given (Group B: n=11) for 12 months. UAE was determined before and at 3, 6 and 12 months after the initiation of ARB. Although the initial BP was significantly higher in Group A (150/83 mmHg) than Group B (127/77 mmHg), BP was decreased to 141/78 mmHg in Group A and slightly, but not significantly, increased to 130/82 mmHg in Group B. In both groups, UAE was significantly decreased after ARB treatment (to 89% of the basal value in Group A and to 40.5% of the basal value in Group B) and did not differ each other and the amount of decrease did not differ significantly between the two groups. These results suggest that combination therapy with an ARB and CCB is very effective in lowering BP and UAE in cases in which BP is not well controlled, while, even in patients with a sufficient BP control of <130/85 mmHg, the use of ARB singly resulted in a significant decrease in UAE without a further decrease in BP, implying that the ARB had a renoprotective action independent of changes in BP.

Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart failure

Omapatrilat (OMP) is a novel mixed inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP), the enzyme that metabolizes natriuretic peptides. Congestive heart failure (CHF) is characterized by excessive sodium retention, attributed to both an excessive effect of angiotensin II and diminished responsiveness to natriuretic peptides. In this study, we examined the acute and chronic renal and cardiac effects of OMP in rats with compensated [urinary sodium excretion (UNaV) > 1,200 microeq/day] and decompensated (UNaV < 100 microeq/day) CHF, induced by a surgical aortocaval fistula (ACF). Bolus injection of OMP (10 mg/kg) to sham controls produced significant diuretic and natriuretic responses [UNaV increased from 0.67 +/- 0.19 to 3.27 +/- 1.35 microeq/min, P < 0.05; fractional sodium excretion (FENa) increased from 0.23 +/- 0.06 to 0.95 +/- 0.34%, P < 0.01] despite a significant decline in blood pressure (BP). Rats with compensated CHF displayed blunted diuresis and natriuresis to this dose of OMP but a significant decrease in BP. However, in rats with decompensated CHF, OMP induced significant natriuresis (FENa increased from 0.18 +/- 0.15 to 0.82 +/- 0.26%, P < 0.05) despite a further decrease in BP (from 90 +/- 9 to 71 +/- 6 mmHg, P < 0.01). Two weeks after ACF, the heart/body weight ratio was significantly greater in rats with CHF than controls (0.51 +/- 0.026 vs. 0.30 +/- 0.004%, P < 0.0001), and UNaV was significantly lower. Immediate or late (1 or 6 days after ACF) OMP treatment in the drinking water (140 mg/l) reduced cardiac hypertrophy to 0.41-0.43% (P < 0.01) and induced natriuresis. These results suggest that OMP improves both sodium balance and cardiac remodeling and might be advantageous to ACE inhibitors for the treatment of decompensated CHF.

Strict dietary sodium reduction worsens insulin sensitivity by increasing sympathetic nervous activity in patients with primary hypertension

To assess the effects of sodium reduction on insulin sensitivity in hypertension, we examined the change of insulin sensitivity after two degrees of dietary sodium restriction by the euglycemic hyperinsulinemic glucose clamp method in 12 subjects with primary hypertension. A controlled period of 1 week, when the subjects were taking a normal sodium diet, was followed by a randomized crossover study in which the subjects were placed on either moderate or strict reduced sodium diets for 1 week. The result of the 1-week moderate dietary sodium reduction from 200 to 100 mmol/day showed significant decreases in systolic and diastolic blood pressure by 6.5 and 5.0 mm Hg, respectively. Strict dietary sodium reduction to 30 mmol/day for 1 week resulted in no further decrease in blood pressure, but it increased plasma insulin by 40.6% without changing plasma glucose. There were no changes in glucose infusion rate (GIR) or insulin sensitivity index (ISI), which is a measure of GIR divided by plasma insulin, after moderate dietary sodium reduction. However, strict dietary sodium reduction induced decreases in GIR by 19.8% (from 1318 ± 189 to 1057 ± 173 μmol/m 2/min; P < .01), and ISI by 20.5% (from 16.6 ± 2.1 to 13.2 ± 1.9 μmol/m 2/min/μU/mL; P < .01) with a paralleled increase of plasma norepinephrine by 90.0% (from 150.5 ± 61.6 to 287.3 ± 114.9 pg/mL; P < .01). These results indicate that dietary sodium restriction leads to a deterioration of insulin sensitivity when plasma norepinephrine levels increase, and suggest that moderate dietary sodium reduction may lower blood pressure without a distinct adverse effect on glucose metabolism in subjects with primary hypertension.

Isradipine

Since the earlier review in Drugs substantial additional data have accumulated regarding the antihypertensive efficacy of isradipine in various clinical situations, as well as data on its clinical effects in atherosclerosis. Recent therapeutic trials confirm that the efficacy of isradipine in the treatment of patients with mainly mild to moderate hypertension, when administered orally as a conventional or modified release preparation, is similar to that of titrated dosages of amlodipine, felodipine, nifedipine, diltiazem, captopril, methyldopa, metoprolol, prazosin and hydrochlorothiazide. A further decrease in blood pressure can be expected when isradipine is combined with another antihypertensive drug in patients who have not responded adequately to monotherapy. Initial studies have shown that intravenous isradipine is effective in controlling hypertension following coronary artery bypass graft surgery and that it appears useful in the treatment of intraoperative hypertension and hypertensive crisis, and in hypertensive disorders in pregnancy, when administered orally or intravenously. A large study, the Multicentre Isradipine Diuretic Atherosclerosis Study (MIDAS), was designed to compare the efficacy of isradipine and hydrochlorothiazide in reducing the rate of progression of carotid artery wall thickness, measured by B-mode ultrasound, as a surrogate for early atherosclerosis. Results indicated that wall thickness increased significantly less with isradipine than hydrochlorothiazide after 6 months of therapy. Thereafter the rate of progression remained parallel for the remainder of the 3-year trial. The confirmation of its antihypertensive efficacy, along with its favourable haemodynamic profile and reversal of left ventricular hypertrophy, minimal effect on glucose and lipid metabolism, preservation of quality of life and good tolerability, makes isradipine a suitable drug for the treatment of most patients with mild to moderate hypertension.

Calcium Channel Blockers as Second-Line Therapy in Thiazide-Resistant Hypertension

In Reply.— Whether a diuretic added to a calcium antagonist or calcium antagonist added to diuretic is additive or synergistic is controversial and requires a well-designed study to answer the question. 1 Studies with diltiazem, 2 verapamil, 3 and nifedipine 4 in which a diuretic was added to a calcium antagonist have shown no additional hypotensive effects. However, two other studies have documented a further decrease in blood pressure with a diuretic. 5,6 The acute natriuresis may be dependent on the amount of sodium intake, whereas the antihypertensive effects are present regardless of the sodium intake. 7 The continued natriuretic effect of calcium antagonists 8 may be important in preventing fluid accumulation and reducing the hypotensive effect of an added diuretic. Recently, a multicenter factorial-design trial demonstrated that a slow-release formulation of diltiazem hydrochloride in combination with hydrochlorothiazide is additive. 9 However, we are unaware of studies, other than ours, 10 in which a calcium antagonist was added to a diuretic.

Physiological and immunopathological consequences of active immunization of spontaneously hypertensive and normotensive rats against murine renin.

Spontaneously hypertensive Okamoto-strain rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were actively immunized with mouse renin to investigate the effect on blood pressure of blocking the renin-angiotensinogen reaction. Ten male SHR and 10 male WKY rats were immunized with purified mouse submandibular gland renin. Control rats were immunized with bovine serum albumin. Antirenin antibodies were produced by both SHR and WKY rats, but renin-immunized SHR had higher titers of circulating renin antibodies after three injections. The increase in renin antibody in renin-immunized SHR was associated with a significant drop in blood pressure (tail-cuff method) that became similar to that of the WKY control rats after four injections. The blockade by antirenin immunoglobulins of the renin-angiotensinogen reaction also decreased the blood pressure of normotensive rats. Perfusion of renin-immunized rats with mouse submandibular renin (10 micrograms) in vivo caused no increase in blood pressure. Perfusion of renin-immunized, salt-depleted SHR with converting enzyme inhibitor caused no further decrease in blood pressure but significantly decreased blood pressure in salt-depleted control rats. The presence of circulating renin antibodies was associated with low plasma renin activity (0.31 +/- 0.23 ng angiotensin I [Ang I]/ml/hr). Plasma renin activity was unchanged in control animals (13.1 +/- 3.9 ng Ang I/ml/hr in control SHR, 13.9 +/- 3.2 ng Ang I/ml/hr in control WKY rats). Renin antibody-rich serum produced a dose-dependent inhibition of rat renin enzymatic activity in vitro. The chronic blockade of the renin-angiotensinogen reaction in renin-immunized SHR produced an almost-complete disappearance of Ang II (0.8 %/- 7 fmol/ml; control SHR, 30.6 +/- 15.7 fmol/ml) and a 50% reduction in urinary aldosterone. Renin immunization was never associated with a detectable loss of sodium after either 10 or 24 weeks. The glomerular filtration rate was not decreased 10 weeks after renin immunization, whereas blood pressure was significantly decreased, plasma renin activity was blocked, and renal plasma flow was increased. The ratio of left ventricular weight to body weight after 24 weeks was significantly below control levels in renin-immunized WKY rats and SHR. Histological examination of the kidney of renin-immunized SHR showed a chronic autoimmune interstitial nephritis characterized by the presence of immunoglobulins, mononuclear cell infiltration, and fibrosis around the juxtaglomerular apparatus. These experiments demonstrate that chronic specific blockade of renin decreases blood pressure in a genetic model of hypertension in which the renin-angiotensin system is not directly involved.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparison of nitrendipine with propranolol and its use in combined cardiovascular therapy

New antihypertensive agents with favorable hemodynamic and metabolic profiles have resulted in reappraisal of traditional step-care therapy using diuretics and β blockers. Calcium channel blockers are among the new antihypertensive agents that offer better hemodynamic effect compared with β blockers, and they do not have unwanted metabolic effects as do diuretics. Calcium channel blockers, such as nitrendipine, are effective as monotherapy and in combination with other antihypertensive agents, and are particularly useful in elderly, black and low-renin patients. Preliminary results from a multicenter, double-blind, randomized, parallel study comparing nitrendipine with propranolol in patients over 40 demonstrate similar blood pressure-lowering effectiveness; however, propranolol was associated with a higher incidence of side effects and study withdrawals. In a second study, addition of propranolol to nitrendipine monotherapy produced a further decrease in blood pressure that was sustained over the year of study. These data suggest that nitrendipine provides additional effective and safe antihypertensive therapy, which can be used in place of or in combination with β blockers.

Comparison and additivity of nitrendipine and hydrochlorothiazide in systemic hypertension

Calcium channel blockers are highly effective antihypertensive agents and provide a good alternative to other medications used as initial or monotherapy. Although the calcium channel blockers act as peripheral vasodilators, they are unique among this group of drugs in lowering blood pressure in a sustained manner; several compensatory mechanisms are inhibited by virtue of either direct or indirect effects of these agents. In recent years, hypertension has generally been treated with a step-care approach, the limitations of which are now becoming apparent. Today, 4 classes of agents are effective and well tolerated as single therapy and might therefore be considered as firstline drug therapy: diuretics, β blockers, converting enzyme inhibitors and calcium channel blockers. Preliminary results from an ongoing double-blind randomized trial comparing nitrendipine (a calcium channel blocker) and hydrochlorothiazide (a diuretic) in mild to moderate hypertension will be presented. Results from 63 patients showed the 2 agents to be equivalent in antihypertensive effects and in frequency of adverse reactions. Other data indicate that when nitrendipine and hydrochlorothiazide were combined, a further decrease in blood pressure was observed. Patient characteristics affecting drug choice and clinical situations in which calcium channel blockers can be used most effectively can now often be delineated.

Hormonal and Hemodynamic Responses to Halothane and Enflurane in Spontaneously Hypertensive Rats

Forty-two spontaneously hypertensive rats (SHR) and 42 normotensive Wistar-Kyoto rats (WKY) were anesthetized with either halothane or enflurane. Blood pressure, heart rate, cardiac output, distribution of blood flow, plasma renin activity, and plasma catecholamines were measured to determine in what manner the hypertensive animal responded to these two anesthetics. Major findings of the study were that plasma renin activity did not increase in the SHR despite a 25% reduction in MAP. The infusion of saralasin, an angiotensin II antagonist, resulted in a further decrease in blood pressure in SHR anesthetized with halothane but not with enflurane. Plasma catecholamine concentrations were elevated in the awake SHR and were decreased in SHR anesthetized with enflurane. Both halothane and enflurane anesthesia resulted in similar alterations in blood flow in the SHR. The normotensive WKY responded to halothane and enflurane in a different manner than the SHR. Plasma renin activity increased with the decrease in blood pressure with both agents. A further decrease in blood pressure occurred with saralasin infusion in WKY anesthetized with halothane or enflurane. Significant blood flow alterations occurred in the WKY anesthetized with both agents, but enflurane caused the greatest changes. The SHR may prove useful in examining the effects of anesthetic agents and other drugs so that we may have a better understanding of the perioperative management of the patients with essential hypertension.

An investigation into the selectivity of a novel series of benzoquinolizines for alpha 2-adrenoceptors in vivo.

The potencies and selectivities of a novel series of benzoquinolizines for the alpha 2-adrenoceptor have been investigated in the rat in comparison with yohimbine and indoramin. Peripheral postjunctional alpha 2- and alpha 1-adrenoceptor blockade was measured as the reversal of B-HT 933 and methoxamine-induced pressor responses, respectively, in the pithed rat. Peripheral prejunctional alpha 2-adrenoceptor blockade was measured as the reversal of B-HT 933-induced inhibition of an electrically evoked tachycardia in the pithed rat. Central alpha 2-adrenoceptor blockade was measured as a reversal of the hypotension induced in anaesthetized rats by central (i.c.v.) administration of clonidine. Wy 25309, Wy 26392, Wy 26703 and yohimbine (0.3-3 mg kg-1 i.v.) evoked dose-dependent shifts to the right of the dose-response curves to B-HT 933 whilst having minimal effects on the methoxamine dose-response curve. The selectivity for alpha 2-adrenoceptors increased with the dose of antagonist administered. In general, the order of selectivity was Wy 25309 greater than Wy 26392 greater than Wy 26703 greater than yohimbine. Indoramin (1 mg kg-1 i.v.) shifted the methoxamine pressor dose-response curve to the right without affecting the B-HT 933 dose-response curves, confirming its selective alpha 1-antagonist activity. Peripheral administration of all three benzoquinolizines (1-100 micrograms kg-1 i.v.) led to a dose-dependent reversal of the hypotension evoked by central administration of clonidine (500 ng i.c.v.). The reversal was incomplete, higher doses causing a further decrease in blood pressure. A similar degree of hypotension induced by the ganglion blocking agent chlorisondamine (1 mg kg- I i.v.) was not reversed by the benzoquinolizines. 9 It is concluded that Wy 25309, Wy 26392 and Wy 26703 are selective alpha 2-adrenoceptor antagonists which readily penetrate the CNS.

NEUROENDOCRINE ASPECTS OF CENTRALLY ACTING HYPOTENSIVE DRUGS

1 The effects of chronic treatment with methyldopa on plasma prolactin (PRL) levels and of the acute administration of guanfacine on growth hormone (GH) release in acromegalic patients were investigated. 2 Elevated plasma PRL concentrations were observed in five of eight patients during chronic treatment with methyldopa (750 mg/day) for 3–8 months. Three male patients complained of loss of libido and/or impotence. Addition of bromocriptine (7.5 mg/day) to methyldopa therapy normalized the PRL levels and sexual function, while it resulted in a further decrease in blood pressure. 3 Guanfacine as an acute test dose is a strong stimulator of GH secretion. We investigated the effect of guanfacine (2 mg orally) on plasma GH levels in six acromegalic patients. In five patients, the elevated plasma GH levels showed a paradoxical decrease from 90 to 180 min after the administration of the drug, while blood pressure remained unchanged. 4 Guanfacine appears to be a safe drug in patients with GH-secreting pituitary tumours and may possibly be beneficial.

Neurogenic activity--angiotensin II interaction during the development and maintenance of renal hypertension in the rat.

1. Pentolinium tartrate (a ganglionic blocker) was injected in conscious rats during the early and late phases of two-kidney renal hypertension produced by aortic ligation. 2. In the early phase ( 5 days after aortic ligation), ganglionic blockade resulted in a decrease in blood pressure equal to that obtained in normotensive rats. Later, at days 12 and 40, for equally severe hypertension, ganglion blockade resulted in a greater decrease in blood pressure. 3. A 30 min infusion of [Sar1, Ala8]angiotensin II during the pentolinium-induced nadir in blood pressure resulted in a further decrease in blood pressure at day 5. Later, at days 12 and 40, this effect was smaller. 4. A 300 min infusion of [Sar1, Ala8]angiotensin II normalized the blood pressure in hypertensive rats at day 40. This delay response may be secondary to a central effect of the antagonist, reducing neurogenic tone or peripheral antagonism of locally generated angiotensin II in the blood vessel walls. 5. At day 40, removal of the small left kidney resulted in a greater decrease in blood pressure. This suggests the presence of a renal factor other than renin in the chronic phase of this hypertension.

Renal hemodynamics during hyperthermia caused by exposure to high environmental temperature.

The GFR (glomerular filtration rate) and RPF (renal plasma flow), following an initial increase, fell significantly after 3–4 hr exposure of anesthetized dogs to an air temperature of 49 C. This alteration occurred with either dehydration or hydration present. Creatinine clearance was used as a measure of GFR and p-aminohippuric acid clearance at low plasma levels was used as a measure of RPF. Rectal temperature averaged 43 C at the conclusion of the experiment. The hematocrit increased 14%. The alteration in renal hemodynamics was shown to be due to a mild fall in mean systemic blood pressure, and a concomitant early decrease in intrarenal resistance followed a further decrease in blood pressure, combined with a progressively increasing intrarenal resistance. It can be concluded that while the fall in blood pressure, increasing intrarenal resistance during the latter part of the exposure, and decreased GFR and RPF are resultants of hyperthermia, the massive loss of plasma volume and increase in hematocrit previously reported in hyperthermia produced with heating pads (largely conductive heating) need not occur. Such major changes may be ascribed to tissue damage rather than to hyperthermia, per se.