The effects of treatment and of withdrawal of treatment with guanfacine and clonidine on blood pressure and heart rate in normotensive and renal hypertensive rats.

Disagreement in the literature about the occurrence of rebound hypertension (hypertensive overshoot) in animal models initiated this investigation. Oral doses of clonidine (0.03 mg kg-1) or guanfacine (0.3 mg kg-1) were administered twice daily during three weeks to groups of normotensive and renal hypertensive rats. Blood pressure and heart rate were measured immediately before and 3 h after the first daily dose, and compared with values obtained from placebo-treated control rats. Treatment with either drug induced large daily fluctuations rather than sustained falls in blood pressure. In the normotensive, but not in the hypertensive groups, the morning blood pressures measured before the first daily dose were significantly elevated over those of the control groups after 9 and 5 days of treatment with clonidine or guanfacine. This elevation persisted for 3 days after drug withdrawal. It is concluded that in the rat the duration of action of both drugs was short, so that twice daily administration of both drugs similarly produced large daily fluctuations rather than sustained falls in blood pressure. Blood pressure rises developed during treatment rather than after withdrawal in normotensive rats only. Therefore, this type of study does not relate well to the human situation and different experimental approaches to this problem are needed.     

The effects of treatment and of withdrawal of treatment with guanfacine and clonidine on blood pressure and heart rate in normotensive and renal hypertensive rats

Disagreement in the literature about the occurrence of rebound hypertension (hypertensive overshoot) in animal models initiated this investigation. Oral doses of clonidine (0.03 mg kg^?1) or guanfacine (0.3 mg kg^?1) were administered twice daily during three weeks to groups of normotensive and renal hypertensive rats. Blood pressure and heart rate were measured immediately before and 3 h after the first daily dose, and compared with values obtained from placebo-treated control rats. Treatment with either drug induced large daily fluctuations rather than sustained falls in blood pressure. In the normotensive, but not in the hypertensive groups, the morning blood pressures measured before the first daily dose were significantly elevated over those of the control groups after 9 and 5 days of treatment with clonidine or guanfacine. This elevation persisted for 3 days after drug withdrawal. It is concluded that in the rat the duration of action of both drugs was short, so that twice daily administration of both drugs similarly produced large daily fluctuations rather than sustained falls in blood pressure. Blood pressure rises developed during treatment rather than after withdrawal in normotensive rats only. Therefore, this type of study does not relate well to the human situation and different experimental approaches to this problem are needed.     

甲基莲心碱的降压作用

甲基莲心碱对麻醉、清醒的正常大鼠,肾性、D0CA盐型高血压大鼠,麻醉猫、清醒正常家兔都能引起快速、剂量依赖性降压作用,猫椎动脉注射及脑室内注射甲基莲心碱0.6mg/kg无明显降压作用。表明甲基莲心碱是一种有效的抗高血压药,对血管平滑肌有直接扩张作用。     

Acute and chronic sympathoinhibition on carotid artery diameter of spontaneously hypertensive rats: effects of clonidine and flesinoxan

1. Hypertensive conduit arteries are thicker and stiffer than those of normotensive controls. Whether they are specifically sensitive to central sympathoinhibition has never been investigated. 2. The effects of acute (24 h infusion) and chronic (4 week infusion) treatments with clonidine (0.01 and 0.1 mg/kg per day) and flesinoxan (1 and 3 mg/kg per day) on carotid artery diameter were investigated in spontaneously hypertensive rats. At the end of treatment, blood pressure (BP) was recorded in the rats while they were conscious. Rats were then anaesthetized for carotid artery diameter measurements using an ultrasonic echotracking device. 3. In conscious rats, clonidine significantly decreased BP and heart rate (HR) following acute but not chronic treatment. In contrast, flesinoxan significantly decreased BP following both the acute and chronic treatment. In anaesthetized animals, the two agents have opposite effects on isobaric carotid artery diameter, with a decrease under clonidine and an increase under flesinoxan. After 4 weeks infusion, the reactivity of aortic rings was studied in organ chambers. Flesinoxan, but not clonidine, caused the relaxation of potassium chloride precontracted aortic segments. 4. The results indicate that although clonidine and flesinoxan are centrally acting antihypertensive agents, the drug-induced changes in isobaric carotid diameter may be influenced by local factors independent of the central action of the two drugs.     

Effects of pentobarbitone and decerebration on the clonidine-induced circulatory changes.

Clonidine 5 and 15 mug/kg i.v. was given to conscious rats, to rats under pentobarbitone anaesthesia and to decerebrated rats. Clonidine 100 mug/kg was given to conscious and to decerebrated rats. Blood pressure and heart rate were recorded via indwelling catheters. The low dose of clonidine gave virtually no response in the conscious rats but produced hypotension and bradycardia in decerebrated and in anaesthetized rats. After clonidine 15 mug/kg the blood pressure of decerebrated rats decreased further, while conscious and anaesthetized rats showed a hypertensive response. The basal blood pressure and heart rate were significantly higher in the decerebrated rats than in the conscious rats. After the highest dose of clonidine, however, the blood pressure of the decerebrated rats decreased below the basal level of the conscious rats and the blood pressure of the conscious rats increased above the basal level of the decerebrated rats. The results suggest that the hypotensive response is caused by a mechanism located in the medulla oblongata. At higher concentrations clonidine may elicit a hypertensive effect by activating suprabulbar centers. The importance of this suprabulbar effect is attenuated by pentobarbitone anaesthesia.     

A comparison of the dose-response effects of captopril in anesthetized normotensive and renovascular hypertensive rats

1. Dose-response effects of captopril in an acute model of renovascular hypertension in the anaesthetized rat and in normotensive anaesthetized rats were compared. 2. Intravenous infusions of captopril lowered the blood pressure of both hypertensive and normotensive rats, its minimal active dose being about 0.05 mg/kg. 3. The 0.1 mg/kg dose of captopril normalized the blood pressure of hypertensive rats. 4. The model described herein might be useful for screening inhibitors of the angiotensin-converting enzyme.     

Guanfacine and clonidine: antihypertensive and withdrawal characteristics after continuous infusion and its interruption in the spontaneously hypertensive and normotensive rat

Summary In conscious unrestrained spontaneously hypertensive and normotensive rats, prepared with permanently indwelling abdominal aortic catheters, the effects on blood pressure and heart rate of a 12-day continuous subcutaneous infusion of guanfacine (10 mg/kg/day) and clonidine (500 g/kg/day) and sudden interruption of these treatments were studied. Both drugs significantly and consistently reduced the mean arterial pressure and heart rate throughout the infusion period in the SH rats, but not in the normotensive animals. The magnitude of the effects of both drugs in the SH rat were similar. Following withdrawal of treatment with guanfacine, a discontinuation syndrome was evoked, much less severe than that observed after suspension of the infusion with clonidine. The withdrawal syndromes were characterized by an overshoot of heart rate and a period of blood pressure lability. In spite of the ineffectiveness of guanfacine and clonidine to reduce blood pressure and heart rate consistently in the normotensive rat, similar withdrawal patterns as those found in the SH rat were observed. These findings are in general agreement with the results previously found in clinical studies in hypertensive patients. The spontaneously hypertensive rat may prove a suitable animal model for pre-clinical studies of discontinuation symptoms after cessation of treatment with antihypertensive drugs.     

NORMOTENSIVE WISTAR RATS DIFFER FROM SPONTANEOUSLY HYPERTENSIVE AND RENAL HYPERTENSIVE RATS IN THEIR CARDIOVASCULAR RESPONSES TO OPIOID AGONISTS

1. The effects of three opioid receptor agonists on the blood pressure and heart rate of anaesthetized normotensive, spontaneously hypertensive and renal hypertensive rats were measured. 2. Mu agonist morphiceptin i.c.v. induced a pressor response and increase in heart rate in hypertensive rats, but hypotension in normotensive rats. After intravenous (i.v.) injection, morphiceptin produced a hypotensive response in all three groups of rats. 3. In contrast, the delta agonist DTLET i.c.v. decreased blood pressure and heart rate in hypertensive rats, but increased both pressure and beat rate in normotensive rats. After i.v. injections DTLET produced a hypertensive response and increase in heart rate in all groups of rats. 4. Kappa agonist U-50, 488H given i.c.v. induced effects similar to morphiceptin: an increase in blood pressure and heart rate in hypertensive and a decrease in normotensive rats. After i.v. injections U-50, 488H produced decreases in blood pressure and heart rate in all treated groups of rats. 5. Pretreatment with naloxone antagonized the activity of morphiceptin but prevented only the stimulating effect of DTLET in normotensive rats. Cardiovascular actions of U-50, 488H were not blocked by naloxone. 6. The results suggest that opioid agonists exert similar changes in cardiovascular function at central and peripheral sites in both models of experimental hypertension and these effects are different in normotensive rats.     

The effects of intracerebroventricular injection of clonidine on conditioned pressor and adrenergic responses in rats

Studies from this laboratory have shown that the first filial offspring of female spontaneously-hypertensive rats and male Wistar-Kyoto (WKY) normotensive rats develop stress-induced hypertension. The present study sought to examine the effects of intracerebroventricular administration of clonidine (8 micrograms) on cardiovascular and sympathoadrenal responses to aversive classical conditioning in these borderline hypertensive rats (BHR) and in normotensive WKY control rats. Clonidine caused significant reductions in resting arterial pressure, vascular resistance, heart rate and concentrations of epinephrine (E) in plasma for both hypertensive and normotensive rats. Central administration of normal saline to control rats of each strain did not alter basal cardiovascular or sympathoadrenal function. The presentation of a conditioned stimulus (CS) elicited a significant increase in arterial pressure and total peripheral resistance in hypertensive rats treated with saline and clonidine and in normotensive rats treated with saline. In contrast, normotensive rats treated with clonidine showed no increases in arterial pressure or vascular resistance following the onset of the conditioned stimulus. The aversive conditioning session instigated significant increases in the concentrations of norepinephrine (NE) and E in plasma in saline-treated rats. Hypertensive and normotensive rats treated with clonidine-showed a blunted increase in plasma concentrations of NE and E during this period; however, concentrations of E in hypertensive rats increased significantly from the baseline period after injection. These data suggest that an abnormality in central alpha 2-adrenoceptor-mediated inhibition of sympathoadrenal discharge and sympathetic vasomotor tone may predispose the hypertensive rat to develop stress-induced hypertension.     

DIFFICULTIES IN DETECTING PARATHYROID HYPERTENSIVE FACTOR IN THE RAT

1. Parathyroid hypertensive factor (PHF) has been implicated in the pathogenesis of several forms of hypertension. We aimed to establish a PHF bioassay using spontaneously hypertensive rat (SHR) plasma. 2. Spontaneously hypertensive rats were confirmed hypertensive and their plasma was dialysed and injected into anaesthetized normotensive rats. 3. Haemodynamic responses to injected SHR plasma were uninterpretable during pentobarbital anaesthesia due to blood pressure (BP) fluctuation. Under halothane anaesthesia, BP was stable but did not rise following SHR plasma injection. Using filtered, undialysed plasma and a different brand of pentobarbital, no consistent BP response was observed following SHR plasma injection. 4. We were unable to detect PHF in the SHR.     

Withdrawal syndrome upon cessation of chronic clonidine treatment in rats.

Clinical reports indicate that cessation of treatment with the antihypertensive agent clonidine is associated with a withdrawal syndrome which may include a hypertensive overshoot of critical proportions. We have attempted to produce an animal model of this syndrome in rats. Rats were treated with clonidine in the drinking water (5 microgram/ml; total dose 300-500 microgram/kg/day) which produced a significant (approx. 20%) decrease in heart rate and blood pressure. Within 24 h of cessation of treatment a significantly greater (approximately 100 beats/min) heart rate was seen in treated animals than in control animals when measurements were made in conscious animals. No hypertensive overshoot was observed. Cessation of treatment was associated with an increase in sympatho-adrenal tone as shown by a trans-synaptic induction of adrenal tyrosine hydroxylase activity. Adrenal denervation prevented the rise in adrenal tyrosine hydroxylase seen after cessation of treatment. Administration of clonidine to pregnant rats (10th day until term) did not alter the development of adrenal tyrosine hydroxylase in the offspring. The data indicate that a withdrawal syndrome is produced upon cessation of chronic clonidine treatment.     

DIFFERENCES IN ARACHIDONIC ACID METABOLISM AND EFFECTS OF ASPIRIN BETWEEN ONE- AND TWO-KIDNEY GOLDBLATT HYPERTENSIVE RATS

Vasodepressor responses to prostacyclin, nitroprusside and arachidonic acid were compared in two groups of anaesthetized, two-kidney, one-clip Goldblatt rats. The groups were composed of rats which had high blood pressure (greater than 150 mmHg systolic) or normal blood pressure (less than 140 mmHg systolic). The vasodepressor effects of prostacyclin and nitroprusside and arachidonic acid did not differ significantly between hypertensive and normotensive groups when measured as percentages of resting blood pressure. Thus, in contrast to one-kidney Goldblatt hypertensive rats, there is no evidence for increased vascular conversion of arachidonic acid to prostacyclin in the two-kidney hypertensive model. The effect of cyclo-oxygenase inhibition on development of hypertension in one- and two-kidney Goldblatt rats was also studied by treating them daily with aspirin (200 mg/kg orally) from 3 days before until 3 weeks after clipping the renal artery. Aspirin-treated two-kidney rats developed significantly higher blood pressures than vehicle-treated controls, but the blood pressures of aspirin-treated one-kidney rats increased less after clipping than those of vehicle-treated controls. It appears paradoxical that transformation of arachidonic acid to prostacyclin is increased, while aspirin has a blood pressure lowering effect in one-kidney Goldblatt rats. It is suggested that there might be a more fundamental disturbance in arachidonate metabolism in hypertension which might contribute to increased vascular reactivity.     

Effect of tissue norepinephrine depletion by 6-hydroxydopamine on blood pressure in spontaneously hypertensive rats

Blood pressure was studied in normotensive and spontaneously hypertensive rats (SHR) in which catecholamine depletion had been produced by 6-hydroxydopamine. After i.v. administration of 80–200 mg/kg 6-hydroxydopamine, norepinephrine (NE) levels in heart, spleen, and kidney were markedly reduced (14–66% of control value) while brain NE remained unchanged. These doses did not affect development of hypertension in SHR or the blood pressure in normotensive control rats during a 20 day period of study. A transient decrease of blood pressure was observed acutely (1–3 days) after an 80 mg/kg dose in normotensive and hypertensive animals. Depletion of NE in the brainstem (to 33–42% of control value) after intraventricular injection of 6-hydroxydopamine, 50–300 μg, had no effect on blood pressure of SHR and normotensive rats. It is concluded that only a small portion of tissue NE content is sufficient for development and maintenance of hypertension in the SHR.     

The effect of prostaglandin E2 on the arterial blood pressure of normotensive and spontaneously hypertensive rats

1 In anaesthetized rats, injection of prostaglandin E(2) (0.5-5.0 mug/kg i.v.) caused a dose-dependent vasodepressor response. The magnitude of response was significantly greater in spontaneously hypertensive rats than in normotensive rats.2 In spontaneously hypertensive rats, the magnitude of the prostaglandin-induced depressor response was closely correlated with blood pressure. The higher the blood pressure, the greater was the response evoked by prostaglandin.3 In spontaneously hypertensive rats, a combination of guanethidine plus hydralazine reduced both blood pressure and prostaglandin-induced depressor responses.4 Spontaneously hypertensive rats and normotensive rats did not differ in the magnitude of their vasodepressor responses to intravenously administered acetylcholine or isoprenaline.     

Cardiovascular effects of 6-hydroxydopamine injected into a lateral brain ventricle of the rat

Summary 6-Hydroxydopamine (6-OH-DA) was injected into the left lateral brain ventricle of normotensive, DOCA/NaCl or spontaneously hypertensive rats, and its effect on heart rate and blood pressure was studied. A single injection of 250 g 6-OH-DA or 3 successive administrations of the same dose caused a reduction of noradrenaline content and tyrosine hydroxylase activity in several parts of the brain to 10–50% of the control values, indicating a considerable destruction of central adrenergic neurons. Heart rate and blood pressure decreased within 10 to 20 min after a single intraventricular injection of 6-OH-DA and both parameters returned to normal after 7 h. This effect was equally observed in normotensive and both types of hypertensive rats and regardless of whether the animals were conscious or anaesthetized. It was prevented by a prior intraventricular injection of phentolamine; this suggests that it is mediated by central alpha-adrenoceptors. The 6-OH-DA-induced bradycardia and hypotension were not influenced by a blockade of peripheral muscarinic receptors with scopolamine methylbromide; however, they were accompanied by a decrease of spontaneous discharges in the splanchnic nerve and, therefore, seem to be due to a reduction in peripheral sympathetic tone.The early cardiovascular effects of 6-OH-DA were sometimes followed by a second phase of bradycardia and hypotension. It occurred in normotensive rats 1–2 days after the second or third intraventricular injection of 6-OH-DA, and in spontaneously hypertensive rats already after a single injection. The hypotension of the second phase lasted 5–6 days, the bradycardia showed no recovery during the observation period which was limited to 3 weeks. Such long term cardiovascular effects of intraventricular 6-OH-DA were never observed in DOCA/NaCl hypertensive rats even after repeated administrations of the compound. The results provide evidence for the existence of a central adrenergic regulation of blood pressure and heart rate which seems to differ in normotensive and hypertensive rats.Preliminary results have been presented at the 11 th Spring Meeting of the German Pharmacological Society in Mainz (Haeusler, Gerold and Thoenen, 1970).     

Lysine incorporation in vessels of spontaneously hypertensive rats: effects of adrenergic drugs

Synthesis of vascular proteins was investigated by measurement of the incorporation of ³H-lysine into the protein fractions in arteries in young normotensive or genetically hypertensive rats. The effect of 14 days of antihypertensive therapy with clonidine, propranolol, and phenoxybenzamine was examined. The rate of incorporation of ³H-lysine into the non-collagen protein in internal spermatic and testicular arteries or mesenteric arteries in 8-week old spontaneously hypertensive rats/NIH (SHR/N) and in stroke-prone spontaneously hypertensive rats/NIH (SHR SP/N) was significantly greater than that of Wistar Kyoto rats/NIH (WK/N). S.c. injection of clonidine, 200 μg/kg twice daily decreased the incorporation of tritiated lysine into the non-collagen protein in internal spermatic arteries in each strain and mesenteric arteries in WK/N and SHR SP/N, concomitant with a reduction of development of blood pressure. Similar results were obtained following phenoxybenzamine treatment (3.5 mg/kg s.c. twice daily) and to a lesser extent, following smaller dose of same drug (1 mg/kg s.c. twice daily). Propranolol administration, 3 mg/kg s.c. twice daily, was ineffective in decreasing non-collagen protein synthesis in these small arteries and failed to reduce the blood pressure in any strain. The incorporation rates of tritiated lysine into the collagen and elastin were similar in the examined vessels in each strain treated with saline. Decreased collagen synthesis was observed following clonidine treatment in internal spermatic and testicular arteries in each strain. Other vascular proteins did not change despite the effective antihypertensive treatment. A high incidence of muscular hypertrophy of the media in internal spermatic arteries in SHR/N or SHR SP/N was observed in non-treated and propranolol-treated animals. This hypertrophy was not seen following clonidine or high doses of phenoxybenzamine. These results indicate that increased non-collagen protein synthesis in the small arteries in young genetically hypertensive rats precedes the development of severe hypertensive vascular lesions and may be involved in the pathogenesis of spontaneous hypertension.     

Acute tolerance to clonidine hypotension and bradycardia in normotensive and hypertensive rats

Tolerance to the antihypertensive effect of clonidine has been observed in humans but there are few studies showing either acute or chronic tolerance to clonidine hypotension in experimental animals. We determined whether tachyphylaxis to acute clonidine hypotension could be demonstrated in normotensive Sprague Dawley rats by i.v. injections of 2 repetitive clonidine doses of either 1.5, 3.0, 5.0, or 10.0 micrograms/kg, or in SHR rats by repeated intracerebroventricular injections of 1.5 or 3.0 micrograms/kg, while monitoring arterial blood pressure. Second doses of clonidine were given 30 minutes after recovery of arterial pressure from the first dose. At 3.0 micrograms/kg and greater, the hypotension produced by the second dose was at least 50% less than that elicited by the first dose. By contrast, no acute tachyphylaxis was observed to the decrease in tension caused by clonidine in the transmurally stimulated isolated guinea pig ileum after 2 repeated exposures to clonidine, with intervening wash, at concentrations between 5 X 10(-10) M to 5 X 10(-8) M. Also, no tachyphylaxis occurred to the initial hypertensive phase of clonidine in Sprague Dawley rats.     

Cardiovascular effects in the rat of ketanserin, a novel 5-hydroxytryptamine receptor blocking agent

Following intravenous administration of ketanserin (0.3-10 mg kg-1) to conscious or anaesthetized normotensive and spontaneously hypertensive rats there were dose-dependent blood pressure reductions but no compensatory tachycardia. Intracerebroventricular administration of ketanserin (25-500 microgram) had inconsistent and largely insignificant cardiovascular effects. In a dose range where it produces hypotension ketanserin antagonized the pressor responses to adrenaline and noradrenaline as well as to 5-hydroxytryptamine in monoamine depleted and spinalized rats. It is suggested that the hypotensive action of ketanserin in the rat does not involve a central mechanism but a peripheral alpha-adrenolytic action is implicated.     

前胡丙素对高血压大鼠血压及犬血管阻力的影响

目的　观察前胡丙素(pra C)的降压及对外周血管阻力的影响。方法　在肾型高血压大鼠模型与正常血压大鼠用尾容积法测血压。用RDB III型输液泵连接于麻醉杂种犬,以控制血流量与压力法直接测定锥动脉、冠脉左旋支、股动脉的阻力。结果　pra-C 20 mg·kg^-1·d^-1 ig给药3 0d对肾性高血压大鼠(RHR)降压峰值时间为6h ,从(213±10 )mmHg降至(144.0±1.5)mmHg,降低原水平30% ,持续至20h。pra-C分别以100 μg·kg^-1 及20 μg·kg^-1与pra-E 20 μg·kg^-1iv可降低上述血管的阻力,减慢心率,降低阻力呈剂量相关。结论　pra-C有降压作用,降低犬外周动脉阻力,增加小鼠耐缺氧时间。     

Effects of single and repeated oral administration of MK-421 and captopril on blood pressures in normotensive and experimental hypertensive rats

In the single dose study, the aortic blood pressure in conscious normotensive rats, 2-kidney, 1-clip renal hypertensive rats (2K-RHR), 1-kidney, 1-clip renal hypertensive rats (1K-RHR) or DOCA hypertensive rats was measured for 24 hr after the oral administration of angiotensin converting enzyme (ACE) inhibitors such as MK-421 or captopril. MK-421 at 3 mg/kg and captopril at 10 mg/kg markedly lowered the blood pressure of 2K-RHR. MK-421 at 10 mg/kg and captopril at 30 mg/kg only modestly lowered the blood pressure of 1K-RHR. In contrast, both ACE inhibitors failed to reduce blood pressure in DOCA and normotensive rats. In the repeated dose study, the systolic blood pressures in normotensive rats, 2K-RHR or spontaneously hypertensive rats (SHR) were measured twice a week for 3 weeks treatment of either MK-421 at 3 mg/kg or captopril at 10 mg/kg. Both ACE inhibitors produced significant antihypertensive effects in these model rats, and the effects were sustained throughout the treatment period. The antihypertensive effects in 2K-RHR were greater than those in SHR and normotensive rats. These results indicate that MK-421 and captopril cause the most significant antihypertensive effect in 2K-RHR in which the renin-angiotensin system played a dominant role in blood pressure regulation. The antihypertensive effect of MK-421 was approximately 3 times as potent as that of captopril in these hypertensive models.