The role of prostaglandins in the alpha- and beta-adrenoceptor mediated renin release response to graded renal nerve stimulation

The role of prostaglandins in the renin release response to renal nerve stimulation (RNS) at different intensities was examined in the anaesthetized dog. The animals were divided into two groups receiving either low or high level RNS, defined by the frequencies of stimulation producing reduction in renal blood flow by 5% or less and 50%. Indomethacin or diclofenac sodium (5 mg/kg i.v.), prostaglandin synthesis inhibitors, did not affect the renin release response to high level RNS by 31±8% (P<0.01). Addition of metoprolol, (0.5 mg/kg i.v.) beta-1-adrenoceptor antagonist, to indomethacin or diclofenac sodium resulted in a greater reduction (68±6%P<0.01) of the renin release response to high level RNS compared to that produced by either drug alone. Metoprolol, alone, reduced the renin release response to high level RNS by 37±14% (P<0.05). Phenoxybenzamine (0.6 g·kg^–1·min^–1), alphaadrenoceptor antagonist, into the renal artery practically abolished the renal vasoconstrictor response to high level RNS and reduced the renin release response by 50±7% (P<0.01). Addition of metoprolol to phenoxybenzamine practically abolished the renal vasoconstrictor response and the renin release response to high level RNS; 94±4% (P<0.01). Addition of phenoxybenzamine to indomethacin or diclofenac sodium practically abolished the renal vasoconstrictor response to high level RNS but did not produce any greater reduction of the renin release response than that produced by either drug alone. These findings suggest that low level RNS results in renin release which is not dependent on prostaglandins. High level RNS results in renin release which is partly mediated by beta-1-adrenoceptors and partly related to alpha-adrenoceptor mediated renal vasoconstriction. Prostaglandins are not involved in the beta-adrenoceptor mediated renin release but are involved in the renin release deriving from alpha-adrenoceptor mediated renal vasoconstriction.     

Renin-Angiotensin System beim diabetischen Patienten

Summary We review available data on the activity of the renin-angiotensin system (RAS), responsiveness to angiotensin II (ANG II), ANG II receptor number, and effects of inhibition of the RAS by angiotensin I converting enzyme (ACE) inhibitors in patients with diabetes mellitus. Most authors, including ourselves, observed a normal or enhanced activity of the RAS in metabolically stable diabetics. Increased but also reduced activity of the RAS was described in nephropathic diabetes. This is in contrast to the common suggestion that the RAS of diabetics is generally suppressed and functionally inactive. The last assumption was mainly based on the finding of reduced ANG II receptor numbers in anorectic, severely hyperglycemic rats. These findings could not be reproduced in man, and a higher ANG II receptor concentration on platelets of diabetics goes in parallel with the frequent finding of an enhanced pressor response to infused ANG II in diabetes. This increased responsiveness is most probably of functional importance since the RAS is not suppressed — as one would expect — in the face of a supranormal body sodium content. A number of data also indicate that renal resistance vessels display increased responsiveness to ANG II in diabetics. This may be a reason for hyperfiltration. This notion is further supported by the reduction of albuminuria which is usually observed following inhibition of the RAS with ACE inhibitors, and which may be an index of reduction of glomerular capillary pressure in human diabetes.     

Resetting of pressure-dependent renin release by intrarenal α1-adrenoceptors in conscious dogs

We investigated the influence of a stimulation of intrarenal -adrenoceptors on the relationship between renin release and renal artery pressure in 8 conscious, chronically instrumented dogs receiving a normal salt diet. Renin stimulus-response curves were determined by a stepwise reduction of renal artery pressure down to 70 mm Hg (1) under control conditions, (2) during a bilateral common carotid occlusion combined with an intrarenal prazosin infusion, and (3) during an intrarenal methoxamine infusion. Both drug infusions did not alter resting renal blood flow. (1) The control renin stimulus-response curve revealed a flat portion (platcau-level) around and above the resting blood pressure and a very steep portion (slope) below a well-defined threshold pressure 10–15 mm Hg below the resting blood pressure. (2) An intrarenal -adrenoceptors blockade by prazosin prevented the resetting of the threshold pressure which is regularly observed during bilateral common carotid occlusion. (3) An intrarenal infusion of the -adrenoceptors agonist methoxamine increased the threshold pressure. We suggest that the neural control of renin release within the autoregulatory range of renal blood flow involves two independent mechanisms: the direct release of renin from juxtaglomerular granular cells by -adrenoceptors, and the modulation of the threshold pressure of pressure-dependent renin release by intrarenal -adrenoceptors. The small changes in renal nerve activity necessary to reset the threshold pressure and the close relationship between the threshold pressure and resting blood pressure imply an important function of intrarenal -adrenoceptors in the regulation of renin release. Our results explain controversial observations regarding the role of intrarenal -adrenoceptors in the control of renin release.This study was supported by the German Research Foundation (FG Niere, Kr. 546/5-1, Projekt 4)     

Renin-like (Angiotensinogenase) activity in human eccrine sweat

The presence of renin or renin-like activity (RLA) was demonstrated in human eccrine sweat incubated with purified sheep angiotensinogen, using rat bioassay and angiotensin I radioimmunoassay. Following cholinergic stimulation, sweat RLA was found to range between 0 (unmeasurable) and 266 ng/ml·h, i.e. RLA-values of sweat can be about 10 times higher than those of plasma. Therefore, renin synthesis in sweat glands could be assumed. RLA following activation of -adrenergic receptors by the administration of isoprenaline (Aludrin^®) did not exceed the mean values obtained by cholinergic activation. After \-adrenergic receptor blockade by propranolol (Dociton^®), RLA became unmeasurably low. Higher RLA-values were found after local injection of dibutyryl-c-AMP (90–210 ng/ml·h). The results indicate a \-adrenergic regulation of RLA-release in human sweat glands. Human sweat glands appear to be useful for studying extrarenal renin release.This work was supported by the Deutsche Forschungsgemeinschaft (Da 93/7)     

Renal prostaglandins

Summary This brief review summarizes the important modulatory effects of endogenous renal prostaglandins (PGs) on renal function. A brief survey of current knowledge of renal PG synthesis reveals the shortcomings of biochemical in vitro studies and points out the necessity to improve methods of in vivo assessment. The problem of measuring circulating levels of PGs and the question of the importance of these PGs for renal function are discussed. Renal blood flow is shown to depend on renal PG's in situations of stress but not under basal conditions. However, in this respect the definition of stress has to include even the mild condition of sodium deprivation. An increasing number of disease states is emerging where renal blood flow is shown to depend on cyclooxygenase activity. Angiotensin II infused or synthesized endogenously seems to be the most likely stress mediator causing enhanced renal PG synthesis which opposes its vasoconstrictor activity. The role of PGs in sodium excretion is not well defined and controversial. In man, most available evidence supports a natriuretic role of renal PGs. However, this role can only be demonstrated under well defined conditions. Inhibitors of PG biosynthesis will cause sodium retention. However, following administration of these drugs a new steady state is reached rapidly characterized by suppressed plasma renin activity and aldosterone. Renal PGs alternate vasopressin effect on urine concentration. The mechanism for this is poorly understood and the role of cAMP in this interaction controversial. Recent evidence showing stimulation of renal PG synthesis by vasopressin independent of its pressor effect is presented. While the stimulatory role of kininogen and kinins on renal PG synthesis has been shown the functional consequences have not been sufficiently defined. Moreover, assessment of the activity of the renal kallikrein-kinin system is at present not possible and no physiological role in renal function has as yet been delineated. Regulation of renal renin release involves PGs. Evidence is presented in support of a role of prostacyclin in baroreceptor and macula densa mediated renin release.     

Defining the physiologic and pathophysiologic roles of renin: the role of specific inhibitors

Although renin was identified as playing a role in cardiovascular homeostasis by the experiments of Goldblatt in the 1930's, neither its physiologic role in organs other than the kidney nor its contribution to the genesis of essential hypertension has been defined as yet. It is difficult to interpret studies with converting enzyme inhibitors because of their multiple pharmacologic effects. Specific inhibitors of renin appropriate for clinical investigation would help resolve many questions. Four classes of compounds have been demonstrated to be renin inhibitors of high potency: specific antibody, general peptide inhibitors of acid proteases, analogs of angiotensinogens, and peptides that are related to the amino-terminal sequence of prorenin. Of these, it is likely that angiotensinogen analogs will be the first applied in human studies. The minimal substrate for renin has the sequence: His-Pro-Phe-His-Leu-Leu-Val-Tyr. Variants of this sequence have yielded competitive inhibitors. Recently, remarkably active compounds have been synthesized by reducing the peptide bond that is cleaved by renin, or by incorporating the amino acid statine, found in pepstatin. These compounds have been shown now to be effective in dogs, rats, and monkeys, and most recently, preliminary studies have reported their efficacy in humans. Recent studies with one of these inhibitors, RIP, raise questions concerning both its specificity and site of action.     

Renin localization in segmental renal hypoplasia

Summary The distribuation of renin in two cases of segmental renal hypoplasia was investigated by immunofluorescence and the peroxidase anti-peroxidase (PAP) method using an anti-human renin antiserum. Renin-containing cells were found only in hypoplasic segments in the vicinity of altered glomeruli and small arteries. Well-preserved renal cortex and areas of chronic atrophic pyelonephritis failed to show any demonstrable site of renin production.Whatever is the mechanism of the disease, the characterization of large numbers of renin-containing cells in the affected kidney support a role for the renin-angiotensin system stimulation in this form of hypertension.     

Typical and atypical aspects of renin secretion from juxtaglomerular epithelioid cells

Summary A survey is given about features of renin synthesis and secretion from juxtaglomerular epithelioid cells that are largely atypical as compared to those of other secretory systems. Renin-producing cells have the capability of reversible metaplastic transformation into vascular smooth muscle cells, their secretory granules are very closely related to lysosomes, and they react paradoxically, i.e. with an inhibition instead of a stimulation of renin secretion, to a rise in intracellular free Ca⁺⁺. The modes of renin secretion and activation of the enzyme as well as possible mechanisms involved in adjusting the ratio of secreted active to inactive renin to the current needs of the renin-angiotensin system are discussed.These studies were supported by the German Research Foundation within the Forschergruppe Niere/Heidelberg     

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.     

Responses of plasma renin activity and dopamine-beta-hydroxylase to increased intravascular volume

Summary Circadian variations of plasma renin activity, plasma dopamine-beta-hydroxylase, and urinary aldosterone excretion were measured in man under conditions of high- and low-sodium intake. Plasma renin activity and urinary aldosterone excretion were maximal at 8 a.m. Plasma DBH shows small, biologically insignificant circadian fluctuations. In three subjects on low-salt diets, the values were lower than those in the same subjects on high-salt diets. Expansion of intravascular volume in supine normal volunteers lowered plasma renin and DBH activity, and also resulted in a significant natriuresis. The decline in DBH activity probably reflects a decrease in its release from autonomic nerve endings and thus demonstrates in man an effect of decreasing autonomic activity.