Inhibition of the adrenalectomy-induced increase in plasma renin concentration by vasoconstrictor agents in rats

Summary Plasma renin concentrations in rats increase after bilateral adrenalectomy without sodium substitution. The effects of i.v. infused (asp¹--amid, val⁵)-angiotensin II (1 g/kg min), felypressin (phen², lys⁸-vasopressin) (40 mU/kg min) and phenylephrine (30 g/kg min) were investigated on the increase in plasma renin concentration. These effects of the agents were compared with their actions on blood pressure, heart rate and renal hemodynamics.In rats with destroyed macula densa cells the effect of bilateral adrenalectomy without sodium substitution was also studied. Adrenalectomy still increased the plasma renin concentration. Angiotensin II and felypressin, also depressed under these conditions the elevation of plasma renin concentration caused by adrenalectomy.The mechanism of the adrenalectomy-induced reinin release and its suppression by vasoconstrictor agents is discussed.Supported by DFG Me 541/1     

Suppression of isoprenaline-induced increase in plasma renin concentration by vasoconstrictors in rats with nonfunctioning Macula densa

Summary The mechanism of the increase in plasma renin concentration caused by the -sympathomimetic agent isoprenaline has been further investigated.Rats were pretreated by occluding the left renal artery for 2 hrs, thus rendering the macula densa cells of this kidney nonfunctioning. After contralateral nephrectomy infusion of isoprenaline (1.5 g/kg min) still caused a strong increase in plasma renin concentration. This increase was significantly suppressed by simultaneous infusion of angiotensin II (1.0 g/kg min), the -sympathomimetic amine phenylephrine (60 g/kg min) or octapressin (10 mU/kg min). The results exclude any mediator-role of the macula densa receptors in the isoprenaline-induced release of renin.The possibility of a stimulation of renin release via the baroreceptors or a direct secretomotoric action of isoprenaline is discussed.Supported by Deutsche Forschungsgemeinschaft Me 541/1.     

Increase of free arachidonic acid by furosemide in man as the cause of prostaglandin and renin release

Arachidonic acid (C20 : 4), plasma renin activity (PRA), PGF_2α, and sodium excretion were determined before and after furosemide in men. C20 : 4 and PRA increased (p < 0.005) within 10 min after furosemide. PRA then decreased again whereas C20 : 4 levels remained elevated. Maximal excretion of PGF_2α and sodium occurred 30–60 min after furosemide. Indomethacin prevented the rise of C20 : 4, PRA and PGF_2α after furosemide, leaving sodium excretion unaltered. The release of C20 : 4 is assumed to be the primary mechanism of furosemide to increase PG biosynthesis and renin release.     

In vitro inhibition by synthetic phospholipids of pressor responses to renin

Incubation mixtures containing kidney extracts and standard doses of renin or angiotensin were injected i.v. into awake rats. Pressor responses to injected renin were reduced while those to angiotensin were unaffected. 2 of 5 synthetic phospholipids had the same effects as the kidney extracts; the oleyl and palmityl derivatives were effective while the stearyl, lauryl, and myristyl derivatives were not. By contrast, the prostaglandins E₁ and F_2α both inhibited responsiveness not only to renin but also to angiotensin and norepinephrine. Neither blockade of vascular angiotensin receptors nor suppression of endogenous converting enzyme explains selective inhibition of response to renin. An enzymatic inhibition of renin also appears unlikely since degree of reduction in response was unaffected by duration of incubation. Our results may be due to the formation of micelles on renin molecules in vitro.     

The stimulation of renin secretion by diazoxide in the isolated rat kidney.

The intrarenal effect of diazoxide on renin secretion was examined in the isolated perfused rat kidney. Mean renin secretion measured at 2 min intervals during the continuous infusion of diazoxide for 6 min was consistently higher than the corresponding control values, although this was significantly different at the end of the infusion only. Since renal perfusion pressure during diazoxide infusion and control studies decreased to a similar extent, it is suggested that diazoxide stimulates renin secretion by a direct effect on the juxtaglomerular cell.     

On the mechanism of renin release by restraint stress in rats.

Restraint causes an increase in plasma renin activity (PRA) which is not affected by pretreatment with dl-propranolo (1 mg/kg IP) or sotalol (15 mg/kg IP). These doses of beta-adrenergic blocking agents are effective in suppressing the stimulation of PRA by isoproterenol. Large doses of dl-propranolol (10 mg/kg IP) and d-propranolol (5 mg/kg IP) attenuate the restraint-induced PRA increase. Adrenal demedullectomy does not affect the PRA response to restraint. Renal denervation blunts the PRA rise due to restraint, but not to direct stimulation by the beta-adrenergic agonist, isoproterenol. It is concluded that the increase in PRA during restraint stress in rats is not solely dependent on an intact renal sympathetic innervation. A significant portion of this stress-induced PRA increase appears to involve a non-adrenergic mechanism.     

Inhibition of captopril-induced renin release by angiotensin II

The angiotensin-converting enzyme inhibitor (CEI) captopril has been shown to elevate plasma renin activity (PRA) and prostaglandin E2 levels, and to lower blood pressure and angiotensin II (AII) levels. Renin is secreted in both active and inactive forms; however, the interrelationship of these forms and responses to captopril are unclear. We proposed to determine if PRA rise induced by captopril is due primarily to release from AII inhibition, and if inactive renin is converted to active renin when PRA increases. Seven normal volunteers were given captopril, 50 mg orally, while on a moderately sodium-restricted diet (35 mEq/day). Changes in PRA and total and inactive renin, as well as prostaglandin E2, were measured. Then, on two different occasions, the captopril dose was preceded or followed by infusion of AII, to negate changes in AII induced by CEI. The dose of AII was obtained by dose-response infusion until a minimal increase in blood pressure occurred. Active renin increased with captopril alone, from 8.2 to 48.3 ng/ml/h by 90 min (p less than 0.01). AII completely blocked the rise in PRA induced by captopril, whether given before or after captopril. Inactive renin did not decline as active renin increased over the 90-min study. Therefore, the PRA rise induced by captopril is mediated through a fall in AII levels and loss of feedback on renin-secreting cells. The rise in PRA comes from secretion of active renin rather than conversion from inactive renin.     

Histamine stimulates renin release from the isolated perfused rat kidney

Summary The renal effects of histamine, histamine receptor agonists and antagonists were studied in the isolated rat kidney, which was perfused with a synthetic medium at constant perfusion pressure in a single pass system.Histamine induced a concentration-dependent increase of renin release ranging from a two-fold increase at 0.5 M to a four-fold increase at 10 M. No change in renal vascular resistance, glomerular filtration rate and sodium excretion occurred. Histamine-H₂-antagonists (ranitidine and cimetidine) were more effective to block the response to histamine than was the histamine H₁-antagonist diphenhydramine.Histamine-H₂-agonists (impromidine and dimaprit, 2.5 M each) were potent stimulators of renin release, their effect was blunted by H₂-antagonists.The histamine-H₁-agonist pyridyl-2-ethylamine had a low stimulatory activity at 10 M final concentration, which may reflect partial H₂-agonistic effects.It is concluded that histamine stimulates renin release via H₂-receptor activation.Part of this work was presented at the 8th Internat. Congress of Pharmacology, Tokyo 1981     

The effect of the converting enzyme inhibitor HOE 498 on the renin angiotensin system of normal volunteers

Summary The converting enzyme inhibitor HOE 498 was evaluated in 12 normotensive male volunteers aged 21 to 26. The efficacy of single 5, 10 or 20 mg oral doses in blocking the pressor response to exogenous angiotensin I was tested in 3 of the subjects. All 3 doses of HOE 498 reduced the pressor response to exogenous angiotensin I to below 50% of control within 1,5 h following administration of the drug. Plasma renin and converting enzyme activity, blood angiotensin I, as well as plasma angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of a single dose of 2.5, 5, 10 or 20 mg of HOE 498 to groups of 5 volunteers each. As expected, blood angiotensin I levels and plasma renin activity rose while plasma converting enzyme activity, plasma angiotensin II and aldosterone concentration fell after administration of the drug. While the dose of 2.5 mg did not reduce plasma converting enzyme activity below 20% of control, the higher doses all resulted in plasma converting enzyme inhibition exceeding 90%. No side-effects were observed. It is concluded that in normal volunteers HOE 498 is an effective potent and long-acting converting enzyme inhibitor. Based on these preliminary findings it is expected that 5 mg HOE 948 will turn out to be adequate for therapeutic use.     

Interactions of MEN 935 (adimolol), a long acting beta- and alpha-adrenolytic antihypertensive agent,with postsynaptic alpha-adrenoceptors in different isolated blood vessels — influence of angiotensin II

Summary MEN 935 [1-(3-((3-(1-naphthoxy)-2-hydroxypropyl)amino)-3,3-dimethylpropyl)-2-benzimidazolinone-hydrochloride monohydrate, adimolol] is a long acting antihypertensive agent with beta- and alpha-adrenolytic properties. Preliminary experiments in pithed rats had led to the suggestion that the alpha-adrenolytic activity was of the alpha₂-subtype. The alpha-adrenolytic properties of MEN 935 were now tested in isolated vascular preparations of rat aorta, rabbit vena ischiadica and rabbit vena cava inferior against the selective alpha₁-adrenergic agonist phenylephrine (PE) and the selective alpha₂-adrenergic agonist BHT 920 [2-amino-6-allyl-5,6,7,8,-tetrahydro-4H-thiazolo-(4,5-d)azepine]. The experiments were performed in absence and in presence of 5×10^–9 mol/l angiotensin II (A II).MEN 935 antagonized contractions to phenylephrine as well as those to B-HT 920 in each vessel. A twofold shift to the right of the concentration-response curves to both agonists was obtained with concentrations between 1.9×10^–8 and 1.4×10^–5 mol/l, depending on the vessel under investigation. A II modulated the adrenolytic properties of MEN 935 in each vessel. However, irrespective of the presence or absence of A II, no pharmacologically relevant difference between antagonism against PE or B-HT 920 could be seen. In isolated vessels, MEN 935 exerts a nonselective alpha-adrenergic antagonism.In receptor binding studies in rat cerebellar cortex, MEN 935 showed a K _i of 5.2×10^–7 mol/l at alpha₁-adrenoceptors and a K _i of 1.3×10^–5 mol/l at alpha₂-adrenoceptors. The K _i values were not influenced by 5×10^–9 mol/l A II. These findings demonstrate an alpha₁-preference, but again no alpha-subtype selectivity.Parts of the results were presented at the Spring Meeting of the German Pharmacological Society, 1985, in Mainz, FRG, (Palluk R, Hoefke W, Gaida W (1985) Alpha-adrenolytic properties of MEN 935, a long acting beta- and alpha-adrenolytic antihypertensive agent. Naunyn-Schmiedeberg's Arch Pharmacol 329: R 79)     

Inhibition by alpha-adrenoceptor agonists of renin release in vitro.

A variety of alpha-adrenergic agonists encompassing a broad range of concentrations were used to investigate the existence and nature of a putative alpha-adrenergic mechanism inhibitory to renin release, which may operate at the level of the juxtaglomerular apparatus. For this purpose rat renal cortical tissue incubated in vitro was used. Concentrations of noradrenaline, adrenaline and methoxamine of 10(-6), 10(-5), 10(-4) and 10(-3) M caused significant dose-related inhibition of renin release. The inhibition of release by these doses was reversed completely by 10(-4) M phentolamine. In contrast, phenylephrine, oxymetazoline and clonidine did not inhibit renin release. The results support the concept of an alpha-adrenergic mechanism inhibitory to renin release and show that high concentrations of alpha-adrenergic agonist are required for its operation in vitro. The manner in which this inhibitory mechanism affects renin release under physiological circumstances remains to be demonstrated.     

Inhibition by SQ 20881 of vasopressor response to angiotensin I in conscious animals

A synthetic nonapeptide structurally identical to one of the compounds found in the venom of Bothrops jararaca was studied in unanesthetized rats and dogs. The nonapeptide, administered by various routes, inhibited the vasopressor response induced by angiotensin I, but not that by angiotensin II, in unanesthetized normotensive dogs, and in unanesthetized normotensive or spontaneously hypertensive rats. The activity was presumably the result of inhibition of angiotensin-converting enzyme. This peptide also augmented bradykinin-induced vasodepression in both species.Repeated daily administration of this synthetic nonapeptide for 5 days did not produce tolerance.     

Plasma renin and the antihypertensive effect of 1-Sar-8-Ala-angiotensin II

A specific, competitive antagonist of the pressor action of angiotensin II, 1-Sar-8-Ala-angiotensin II, was tested for its effect on the blood pressure of conscious dogs during the normotensive, malignant-renal-hypertensive and both the acute- and chronic-renal-hypertensive states. The depression of blood pressure caused by 1-Sar-8-Ala-angiotensin II in these canine models was found to be directly proportional to the magnitude of the plasma renin activity irregardless of the method of induction, type, or duration of the hypertension. The results of these studies indicated that hypertension occuring in the presence of supernormal renin levels was in large part due to the pressor action of angiotensin II.     

Effect of angiotensin II and its analogs on uptake and release of 14C-5-hydroxytryptamine by rat brain.

Uptake of 14C-labelled 5-hydroxytryptamine (14C-5-HT) has been investigated by perfusion of the rat brain ventricular system. When angiotensin II was present during perfusion, a dose-dependent inhibition of 14C-5-HT uptake in rat brain was observed. A similar effect was obtained with angiotensin II analogs (8-alanine angiotensin II or 1-dimethylglycine, 8-isoleucine angiotensin II). The inhibitory effect of angiotensin II can be almost completely blocked with 1-dimethylglycine, 8-isoleucine angiotensin II. In washout experiments, the radioactivity remaining in the brain was greater in the presence of angiotensin II.     

Prostaglandin release from vasculature by angiotensin II: dissociation from lipolysis

Prostaglandin (PG) was released from the perfused splenic fat pad (with the spleen removed) by angiotensin (AII) and not by epinephrine or ACTH. The angiotensin antagonist, cysteine-8-AII blocked the AII induced PG release both in the spleen and the splenic fat pad. ACTH stimulated lipolysis from the rabbit spleen fat pad, but catecholamines and AII were ineffective. Thus, the release of PG from the rabbit splenic fat pad does not seem to require enhanced lipolysis nor do lipolytic agents cause the release of bioassayable PG.     

Inhibition of insulin release from the rat pancreas by cyproheptadine and tricyclic antidepressants

Summary Cyproheptadine and the structurally related compounds doxepin and amitriptyline inhibited the insulin release from the perfused rat pancreas. Both early and late insulin secretion induced by a high glucose stimulus (20 mM) were suppressed by cyproheptadine (0.1 and 0.01 mM). Similarly, although less efficiently doxepin (0.1 and 0.01 mM) and amitriptyline (0.1 mM) diminished both phases of secretion.2 hrs after a single injection of cyproheptadine (20 mg/kg) the rat plasma insulin was reduced to 20% of controls. Simultaneously the blood glucose had increased 2.5 fold.The results suggest that the inhibition of insulin release is a common attribute to tricyclic compounds structurally related to cyproheptadine.     

Inhibition by parasympathetic nerve stimulation of the release of the adrenergic transmitter

Summary Isolated rabbit atria were perfused with Tyrode solution containing (+)-amphetamine. Electrical stimulation of the right postganglionic sympathetic fibres caused an output of noradrenaline which was significantly decreased by simultaneous stimulation of the vagus nerves.This work was supported by the Deutsche Forschungsgemeinschaft.     

Sar1-Ala8 angiotensin II blocks renin-angiotensin but not beta-adrenergic dipsogenesis

Continuous, intravenous (IV) infusion (10 μg/min) of Sar¹-Ala⁸ angiotensin II (P-113), an angiotensin II blocking analog, into rats greatly attenuated water intake resulting from IV renin (4 U) and IV angiotensin II (80 μg). P-113 infusion did not attenuate the drinking induced by the subcutaneous (SC) administration of beta-adrenergic agents: isoproterenol (0.05 mg/kg), quinterenol (4 mg/kg), and diazoxide (40 mg/kg). P-113 also functioned as a weak agonist with respect to the drinking response. It was concluded that beta-adrenergic dipsogenesis in not attributable to renin release but does depend upon some unknown renal endocrine factor.     

共同负荷联合输注血管收缩药对腰麻剖宫产术产妇血流动力学及胎儿的影响

目的比较共同负荷联合血管收缩药对腰麻剖宫产术产妇血流动力学及胎儿的影响。方法选择2012年8月-2013年8月在我院待产的单胎足月妊娠产妇150例为研究对象,随机分为E组泵注麻黄碱（8mg/ml）,E＋Ph组泵注麻黄碱复合去氧肾上腺素（麻黄碱4mg/ml＋去氧肾上腺素50μg/ml）,Ph组泵注去氧肾上腺素（100μg/ml）,每组50例。监测麻醉前基础值（T0）、麻醉后1min（T1）、3min（T2）、5min（T3）、10min（T4）、20min（T5）及手术结束时（T6）产妇的收缩压、舒张压、平均动脉压、心率。胎儿娩出即刻进行脐动脉及脐静脉血血气分析,记录胎儿娩出后1min和5min的Apgar评分。结果与T0时比较,E组T2-T5时和E＋Ph组T2-T4时产妇心率明显增快,而Ph组T2-T4时产妇心率明显减慢（P〈0.05）;与T0时比较,T3时3组产妇SBP和DBP明显升高,而T5-T6时3组产妇SBP和DBP呈现下降（P〈0.05）;与Ph组比较,E组T2-T5时和E＋Ph组T2-T4时心率明显增快（P〈0.05）,E组T4时产妇SBP和DBP轻度下降（P〈0.05）。3组产妇动脉血气分析结果比较差异显著（P〈0.05）,E组脐动脉和脐静脉血的pH值和碱剩余分别低于Ph组（P〈0.05）,而PCO2和乳酸浓度分别高于Ph组（均P〈0.05）,E＋Ph组脐动脉和脐静脉血的碱剩余低于Ph组（P〈0.05）,而葡萄糖和乳酸浓度均高于Ph组（P〈0.05）。3组新生儿1min和5min的Apgar评分均大于9分,差异无统计学意义（P〉0.05）。结论共同负荷联合输注血管收缩药能有效维持产妇在腰麻后血流动力学稳定,从胎儿安全性评价指标来看,与麻黄碱单独使用相比,去氧肾上腺素或去氧肾上腺素与麻黄碱联合使用对胎儿血气影响较小,能给胎儿提供更安全的生存环境。