Is the sympathoexcitatory effect of yohimbine determined by brain yohimbine concentration?

Summary Plasma noradrenaline and adrenaline concentrations, plasma renin concentration (PRC), and serum and brain yohimbine concentrations were measured in conscious Sprague-Dawley rats after the s. c. and i. v. injection of yohimbine. The s.c. and i.v. administration of 1 and 3 mg/kg of yohimbine (30 min post-injection) elicited equivalent and dose-related increases in plasma noradrenaline concentration. At 30 min post-injection, the 1 mg/kg dose given s. c. or i. v. did not increase plasma adrenaline concentration or PRC, whereas the 3 mg/kg dose caused comparable increases in plasma adrenaline concentration and PRC when given s. c. or i. v. Brain yohimbine concentration increased in a dose-related manner whereas serum yohimbine concentration was not significantly different 30 min after treatment with the 1 and 3 mg/kg doses regardless of the route of injection. Despite the fact that serum yohimbine concentration was 5-fold greater after i. v. injection as compared to s. c. administration (1 and 3mg/kg doses), brain yohimbine concentrations were comparable after s. c. and i. v. injection and thus not dependent on either the route of administration or serum yohimbine concentration. The fact that the s. c. and i. v. injection of yohimbine lead to comparable dose-related increases in both brain yohimbine concentrations and neuroendocrine responses suggests that increased sympathetic outflow resulted primarily from an action of yohimbine at central, rather than peripheral, a2-adrenoceptors. However, the data also are consistent with a purely peripheral prejunctional action of the 1 mg/kg dose and a combined central and peripheral action of the 3 mg/kg dose. Send offprint requests to T. Kent Keeton at the above address     

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.     

T-type and L-type calcium channel blockers exert opposite effects on renin secretion and renin gene expression in conscious rats

1. This study aimed to investigate and to compare the effects of pharmacological T-type calcium channel and of L-type calcium channel blockade on the renin system. To this end, male healthy Sprague-Dawley rats were treated with the T-channel blocker mibefradil or with the L-channel blocker amlodipine at doses of 5 mg kg⁻¹, 15 mg kg⁻¹ and 45 mg kg⁻¹ per day for four days and their effects on plasma renin activity (PRA) and kidney renin mRNA levels were determined.
2. Whilst amlodipine lowered basal systolic blood pressure at 5 mg kg⁻¹, mibefradil had no effect on basal blood pressure in the whole dose range examined. Amlodipine dose-dependently induced up to 7 fold elevation of PRA and renin mRNA levels. Mibefradil significantly lowered PRA and renin mRNA levels at 5 mg kg⁻¹ and moderately increased both parameters at a dose of 45 mg kg⁻¹, when PRA and renin mRNA levels were increased by 100% and 30%, respectively. In primary cultures of renal juxtaglomerular cells neither amlodipine nor mibefradil (0.1–10 μM) changed renin secretion.
3. In rats unilateral renal artery clips (2K-1C) mibefradil and amlodipine at doses of 15 mg kg⁻¹ day⁻¹ were equally effective in lowering blood pressure. In contrast mibefradil (5 mg kg⁻¹ and 15 mg  kg⁻¹ day⁻¹) significantly attenuated the rise of PRA and renin mRNA levels, whilst amlodipine (15 mg kg⁻¹) additionally elevated the rise of PRA and renin mRNA levels in response to renal artery clipping.
4. These findings suggest that T-type calcium channel blockers can inhibit renin secretion and renin gene expression in vivo, whilst L-type calcium channel blockers act as stimulators of the renin system. Since the inhibitory effect of T-type antagonists is apparent in vivo but not in vitro, one may infer that the effect on the renin system is indirect rather than directly mediated at the level of renal juxtaglomerular cells.

     

Influence of streptozotocin-induced diabetes on blood pressure and on renin formation and release

Summary I.v. injection of 40 mg/kg or 65 mg/kg streptozotocin reliably induced diabetes in female Sprague-Dawley rats, but failed to induce hypertension within the following 42 days. In most animals injected with the higher dose and in some animals injected with the lower dose, the tail blood flow was permanently impaired so that no blood pressure signals could be obtained by tail plethysmography. This phenomenon occurred also when the drug was injected into the jugular vein and thus was not due to a local effect of streptozotocin. 15 days after 65 mg/kg streptozotocin, the mean arterial pressure of the rats was similar to that of controls, when measured in the awake state (carotid cannula) or under ether anaesthesia. 42 days after streptozotocin, under pentobarbital anaesthesia, the blood pressure was again normal in the animals given 40 mg/kg of the drug and depressed in the animals given 65 mg/kg of the drug 42 days previously. The increase of blood pressure induced by 1 g/kg (–)-noradrenaline i.v. was similar in the latter group of animals and in controls.The renal cortical renin concentration was much lower than in controls 42 days after either dose of streptozotocin, while the plasma renin activity was normal (40 mg/kg) or increased (65 mg/kg). The low renal renin content may have been due to the diabetic state, rather than to the drug itself. Adrenal medullary dopamine-beta-hydroxylase activity was increased 42 days after the higher dose of streptozotocin.Supported by the Swiss National Science Foundation, grant Nr. 3.410.078     

Dissociation of blood pressure and sympathetic activation of renin release in sinoaortic-denervated rats

1. Blood pressure (BP) and heart rate (HR) increase 6 and 24 h after sinoaortic baroreceptor denervation (SAD), whereas plasma renin activity (PRA) and renal renin mRNA levels remain unchanged. We postulated that a simultaneous rise in BP could offset the expected activation of renin associated with an increased renal sympathetic discharge secondary to SAD. 2. To test this hypothesis, the increase in BP associated with the onset of SAD was prevented by a continuous infusion of sodium nitroprusside (SNP; 30 microg/kg per h). Changes were measured in five groups of conscious adult male Wistar rats: (i) sham; (ii) SAD; (iii) SAD rats in which the BP was prevented from increasing by infusion of SNP; (iv) sham rats in which the BP was increased by 30% by infusion of phenylephrine (PE; 1.5-2.0 mL/h); and (v) SNP + PE for 3 h by infusion as above. 3. As expected, BP and heart rate (HR) increased significantly following SAD compared with sham rats (152 +/- 4 vs 116 +/- 3 mmHg, respectively, for BP and 503 +/- 6 vs 345 +/- 13 b.p.m., respectively for HR; n = 5; P < 0.05) but remained unchanged when SNP was infused for 3 h (106 +/- 1 mmHg and 455 +/- 9 b.p.m., respectively; n = 5; P < 0.05). 4. Similarly, BP and HR increased with PE infusion compared with PE + SNP (138 +/- 9.9 vs 113 +/- 2.3 mmHg for BP, respectively, and 325 +/- 9 vs 423 +/- 18 b.p.m. for HR, respectively; n = 5; P < 0.05). 5. Plasma renin activity remained unchanged in SAD compared with sham rats (1.67 +/- 0.35 vs 1.05 +/- 0.17 ng angiotensin (Ang) I/mL per h), but increased significantly when hypertension was prevented (5.86 +/- 0.77 ng AngI/mL per h; n = 5; P < 0.05). Renin mRNA levels in the kidneys were unchanged in all groups. 6. These results show that an elevation in BP appears to offset increased renal sympathetic discharge with no change in PRA.     

A comparison of the effects of prazosin and hydrallazine on blood pressure,heart rate and plasma renin activity in conscious renal hypertensive dogs

Prazosin, a novel antihypertensive agent, and hydrallazine have been compared in renal hypertensive dogs. I.v. prazosin (0.1 mg/kg) produced greater falls in blood pressure than hydrallazine (1 mg/kg i.v.) but, in contrast to hydrallazine, did not cause any significant alteration in heart rate or plasma renin activity in these animals. When given orally, prazosin (0.1 mg/kg) produced falls in blood pressure equivalent to those observed with i.v. hydrallazine (1 mg/kg) again without significant tachycardia or plasma renin activation.     

The pharmacokinetic properties of yohimbine in the conscious rat

Summary We used high performance liquid chromatography with fluorescence detection to measure the concentration of yohimbine in serum and brain of conscious Sprague-Dawley rats at various times after the i.v. injection of 1 mg/kg of yohimbine. The serum concentration-time profile of yohimbine was biphasic with a rapid distribution phase (t _1/2 = 0.048 h) followed by a very slow elimination phase (t _1/2 = 16.3 h). The clearance of yohimbine was 11 ml/h·kg^–1, and the volume of distribution was 259 ml/ kg. Increasing doses (0.3, 1 and 3 mg/kg, i.v.) of yohimbine produced non-linear increases in serum yohimbine concentration. Yohimbine entered the brain rapidly (5,000 ng/g at 5 min after 1 mg/kg, i.v.) and disappeared from brain with a t _1/2 of 7.7 h. In contrast to serum yohimbine concentration, increasing doses of yohimbine (0.3, 1 and 3 mg/kg) produced linear increases in brain yohimbine concentration, a phenomenon which is consistent with concentration-dependent binding of yohimbine to plasma proteins. The rapid entry of yohimbine into the brain, the slow rate of elimination of yohimbine from serum and brain and the linear relationship of brain yohimbine concentration as a function of dose should be taken into consideration whenever yohimbine is to be used as a probe of ₂-adrenoceptor function in vivo. Send offprint requests to T. Kent Keeton at the above address     

Arachidonic acid increases and indomethacin decreases plasma renin activity in the rabbit

Plasma renin activity (PRA) was measured in rabbits before and after infusion of the prostaglandin precursor, arachidonic acid (C20:4) and of the prostaglandin synthesis inhibitor, indomethacin. Non-hypotensive doses of C20:4 (10–15 μg/kg/min) increased PRA from 45 ± 7.3 to 91 ± 16 ng/ml/hr (n = 6, p < 0.05). Conversely, indomethacin decreased PRA from 45 ± 11 to 27 ± 6.0 ng/ml/hr (n = 4, p < 0.001). The results suggest a relationship between the renin and prostaglandin systems.     

Lack of adrenergic influence on renin release after furosemide in normal man

Summary The role of the sympathetic nervous system in furosemide-induced renin release was investigated in six normal subjects. After intravenous administration of furosemide, plasma renin concentrations increased more than two-fold within 15 min. Neither replacement of urinary fluid loss by intravenous infusion of saline nor pharmacological betablockade with d,1-propranolol changed the renin response to furosemide. The activity of the sympathetic nervous system, as estimated by measurement of plasma catecholamine concentrations, remained at the reference level after furosemide. It is concluded that the sympathetic nervous system is not involved in renin release after intravenous administration of furosemide.     

Central choline suppresses plasma renin response to graded haemorrhage in rats

Central administration of choline increases blood pressure in normotensive and hypotensive states by increasing plasma concentrations of vasopressin and catecholamines. We hypothesized that choline could also modulate the renin-angiotensin pathway, the third main pressor system in the body. Plasma renin activity (PRA), which serves as an index of the function of the peripheral renin-angiotensin system, was determined in rats subjected to graded haemorrhage following central choline administration. Intracerebroventricular (i.c.v.) injection of choline (12.5-150 microg), a precursor of the neurotransmitter acetylcholine (ACh), inhibited the increase in PRA in rats subjected to graded haemorrhage by sequential removal of 0.55 mL blood/100 g bodyweight. Choline, in the range 50-150 microg, increased blood pressure. Intraperitoneal (i.p.) administration of 150 microg choline failed to alter blood pressure and plasma renin responses to graded haemorrhage. Administration of a higher dose (90 mg/kg, i.p.) of choline decreased blood pressure and enhanced PRA in the first two blood samples obtained during the graded haemorrhage. Physostigmine (10 microg, i.c.v.), ACh (10 microg, i.c.v.), carbamylcholine (10 microg, i.c.v.) and cytidine 5'-diphosphocholine (CDP-choline; 250 microg, i.c.v.) increased blood pressure and attenuated plasma renin responses to graded haemorrhage. Inhibition of PRA by i.c.v. choline was abolished by i.c.v. pretreatment with mecamylamine (50 microg), but not atropine (10 microg). Blood pressure responses to choline (150 microg) were attenuated by pretreatment with both mecamylamine and atropine. Inhibition of PRA in response to central choline administration was associated with enhanced plasma vasopressin and catecholamine responses to graded haemorrhage. Pretreatment of rats with a vasopressin antagonist reversed central choline-induced inhibition of plasma renin responses to graded haemorrhage without altering the blood pressure response. In conclusion, central administration of choline inhibits the plasma renin response to graded haemorrhage. Nicotinic receptor activation and an increase in plasma vasopressin appear to be involved in this effect.     

Yohimbine induces sympathetically mediated renin release in the conscious rat

The preferential alpha 2-adrenergic antagonist yohimbine (4 mg/kg s.c.) caused a time-related increase in serum renin activity and heart rate in conscious Sprague-Dawley rats. Although mean arterial pressure was not decreased significantly over the 2-h period, heart rate was elevated significantly at 15 and 30 min post-injection. In contrast, serum renin activity remained elevated for up to 2 h with a 9-fold and 9.7-fold increase occurring at 30 and 60 min post-injection, respectively. Yohimbine (0.3, 1, 3 and 10 mg/kg s.c.) elicited a dose-related increase in serum renin activity and heart rate (30 min post-injection). The 1 mg/kg dose of yohimbine did not alter blood pressure whereas the 3 mg/kg dose caused a variable decrease in mean arterial pressure. The highest dose of yohimbine (10 mg/kg) significantly lowered blood pressure. The beta-adrenergic receptor antagonist propranolol (1.5 mg/kg s.c.), blocked the renin release and tachycardia caused by yohimbine (1 and 3 mg/kg s.c.), and the ganglionic blocking agent chlorisondamine partially inhibited the renin release elicited by 3 mg/kg (s.c.) of yohimbine. The prostaglandin synthetase inhibitors indomethacin (5 mg/kg s.c.) and meclofenamate (5 mg/kg s.c.) impaired the ability of yohimbine (3 mg/kg) to elevate SRA but did not alter the hemodynamic effects of yohimbine. Thus, the increase in renin release caused by yohimbine appears to be mediated by the sympathetic nervous system. Because the smaller doses of yohimbine increase renin release in the absence of a decrease in mean arterial pressure, it is unlikely that yohimbine stimulates renin release by baroreflex-mediated activation of the renal sympathetic nerves.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma renin activity and renal sodium and water excretion following infusion of arachidonic acid in rats

Plasma renin activity (PRA) and urinary sodium and water excretion were measured following infusion of the prostaglandin (PG) precursor arachiodonic acid (C20 : 4) in normal hydrated rats (saline i.v.: 0.5 ml/hr/100 g body weight) and in rats with moderate volume expansion (saline i.v.: 1.5 ml/hr/100 g body weight). Nonhypotensive doses of C20 : 4 (40–70 μg/min/100 g b.w.) increased PRA in both normal and volume-expanded rats (p < 0.05, and p < 0.025, respectively). In volume-expanded rats, C20 : 4 was followed by reduced urine volume (p < 0.01) and sodium excretion (p < 0.001) in comparison to volume-expanded control rats, whereas in normal hydrated rats these parameters remained unchanged after C20 : 4. The present results indicate that the C20 : 4-stimulated PG-synthetase system can increase PRA independently of the extracellular fluid volume. Futhermore, these results suggest a complex interrelationship between PG-synthetase action, activation of the renal renin—angiotensin system and urinary water and sodium excretion.     

Effect of lithium on plasma renin activity

The effect of lithium on renin secretion and on plasma renin activity (PRA) was studied in the rat. Administration of 3 mmoles/kg of LiCl caused a significant lowering of PRA within one day of beginning treatment and continued throughout the 14 days of lithium administration. Progressive increase of the dose of LiCl from 2 mmoles/kg to 16 mmoles/kg produced lowering of PRA at small doses and elevation of PRA at higher doses of lithium. The increase of PRA by high doses of lithium was abolished by the simultaneous injection of NaCl. Perfusion of the isolated rat kidney with a solution containing LiCl(> 5 mM) caused increased release of renin into the renal vein. Kidneys from rats pretreated with LiCl showed lower rates of renin secretion into the renal vein when perfused with lithium-free solutions. The possible mechanisms of the dual effect of lithium on renin levels are discussed.     

Role of the renin-angiotensin system in the blood pressure rebound to sodium nitroprusside in the conscious rat.

Intravenous infusions of sodium nitroprusside (SNP) at doses of 20, 40 or 80 micrograms/kg min-1 for 30 min produced dose-related decrements in blood pressure in conscious rats fitted with indwelling aortic and vena caval catheters. Immediately upon termination of SNP infusions, blood pressure rebounded to levels which were significantly above pre-SNP control values. The following evidence indicates that the rebound increase in blood pressure was due to increased activity of the renin-angiotensin system: (1) plasma renin activity was increased approximately four-fold by SNP, (2) rebound did not occur in nephrectomized rats, (3) rebound was markedly attenuated in animals treated with an angiotensin converting enzyme inhibitor, SQ14225, (D-3-mercapto-2-methylpropanoyl-L-proline) and (4) beta-adrenergic receptor blockade with propranolol reduced the rebound response. In addition, the magnitude of the rebound following SNP infusions was directly related to the dose of SNP infused. These results are consistent with the hypothesis that renin accumulates during SNP infusion more rapidly than it is metabolized. Consequently, the accumulated renin elicits a hypertensive response when SNP treatment is withdrawn.     

Comparative hypotensive activity of REV 6207 and enalapril in the conscious furosemide-treated monkey

The cardiovascular effects of ascending doses (0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg i.v.) of two angiotensin l-converting enzyme (ACE) inhibitors, REV 6207 and enalapril, were assessed in conscious furosemide-treated (3 mg/kg s.c.) monkeys. Both ACE inhibitors produced a dose-related inhibition of the pressor response to angiotensin l (0.66 μ/kg i.v.) with concomitant decreases in mean arterial pressure and no change in heart rate. The calculated ED₅₀ values for REV 6207 (0.316 mg/kg) and enalapril (0.275 mg/kg) were similar and both abolished the pressor response to angiotensin l at a dose of 3 mg/kg. The results of the study show that REV 6207 is a potent nonsulfhydryl-containing ACE-inhibitor with blood-pressure-lowering activity comparable to enalapril in the conscious monkey with high renin activity.     

Plasma renin concentration in hypertension produced by unilateral renal artery constriction in the rat

1. Plasma renin concentration (PRC) and blood pressure were studied sequentially, 24 h to 42 days post-operatively, in rats subjected to unilateral renal artery constriction without contralateral nephrectomy. 2. The PRC of rats failing to develop hypertension remained normal, whereas the mean PRC of twenty-two rats that became hypertensive was five times normal on day 14 of the study when the hypertension was becoming established. 3. In eleven of the twenty-two rats that became hypertensive, PRC did not exceed the upper limit of normal. In the remaining hypertensive rats, the increase in PRC was not always temporally related to the increase in blood pressure. A significant correlation between PRC and blood pressure did not emerge until day 35 of the study. 4. Despite these anomalies, linear regression analysis of 169 pairs of PRC and blood pressure measurements during the 42 day period of development of hypertension in twenty-two rats revealed a highly significant correlation between log PRC and blood pressure (P smaller than 0.001). 5. It is concluded that factors other than the plasma concentration of renin are involved in the early stages of development of hypertension induced by renal artery constriction. Nevertheless, PRC and blood pressure are intricately related.     

Pharmacokinetics and pharmacodynamics of alprenolol in the treatment of hypertension

Summary Mean steady-state plasma concentrations of alprenolol were studied in relationship to the degree of beta-blockade, in sixteen patients receiving 600 mg daily in divided doses. Steady-state alprenolol concentrations were determined from the area under the plasma concentration-time curve during one eight-hour dosage interval after treatment for six weeks. Beta-blockade during alprenolol treatment was assessed from the chronotropic response to intravenous isoprenaline compared to the response after six weeks of placebo therapy. Although there was interindividual variability in the mean steady-state alprenolol concentration (range 11 — 141 ng/ml), and in the degree of beta-blockade (7-fold), the correlation between the two variables was highly significant (r=0.80, p<0.001). The prescribed dose of alprenolol (mg/kg) was not significantly correlated with the plasma level of alprenolol or the -blockade. The chronotropic effects of isoprenaline during placebo and alprenolol were significantly interrelated (r=0.79, p<0.001).     

Pharmacological evidence that the sympathetic nervous system mediates the increase in secretion of renin produced by p-chloroamphetamine

The increase in plasma renin activity produced by p-chloroamphetamine in unanesthetized rats is blocked by p-chlorophenylalanine and by lesions of the dorsal raphe nucleus and the mediobasal hypothalamus. To determine whether the pathway from these areas of the brain to the kidneys that mediates the renin response is sympathetic, the effect of beta-adrenergic blockade and ganglionic blockade on the renin response to p-chloroamphetamine was studied. The increase in plasma renin activity 60 min after the administration of p-chloroamphetamine (10 mg/kg, i.p.) was prevented by the beta-adrenergic antagonist (-)-propranolol (1 mg/kg, i.p.), but not by (+)-propranolol (1 mg/kg, i.p.), given 30 min before p-chloroamphetamine. Sotalol (30 mg/kg, i.p.) injected 30 min before p-chloroamphetamine also blocked the renin response. The ganglionic-blocking drug chlorisondamine lowered blood pressure and increased plasma renin activity by itself. However, p-chloroamphetamine administered 30 min after chlorisondamine produced no further increase in plasma renin activity. Chlorisondamine, by itself, did not produce maximal secretion of renin, since isoproterenol, 30 min after chlorisondamine, produced a large increase in plasma renin activity. The data indicate that the increase in plasma renin activity produced by p-chloroamphetamine is mediated via the sympathetic nervous system.     

The effects of intravenous L-dopa on plasma renin activity, renal function, and blood pressure in man

Summary L-dopa 7 µg·kg^–1·min^–1 was given intravenously over 2 h to six healthy subjects, controlled by an infusion of saline on a separate occasion, with measurement of plasma renin activity (PRA), urinary sodium and potassium excretion, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), blood pressure, and pulse rate.Mean PRA fell by 50% following L-dopa, which was significantly different from the slight rise which occurred after saline infusion. There was a significant increase in urinary sodium excretion and effective renal plasma flow on infusion of L-dopa. Mean diastolic blood pressure fell during L-dopa infusion, in contrast to the slight increase which occurred during the control study.These observations confirm the anticipated renal dopaminergic effects of L-dopa and also suggest a dopaminergic influence on renin release in man.     

Clonidine-induced increase of renal prostaglandin activity and water diuresis in conscious dogs.

I.v. administration of clonidine to conscious dogs induces a water diuresis with hyposmotic urine and minor effect on electrolyte excretion. The diuresis is preceded by an increased urinary PGE excretion, but no change of urinary ADH output is observed. Plasma renin activity decreases. Both ADH infusion and indomethacin pretreatment inhibit the diuretic effect of clonidine. The results support the hypothesis that clonidine-induced water diuresis is mediated via an anti ADH effect due to increased renal prostaglandin activity. Moreover the results suggest that there is no direct stimulation of renin release by PGE.