Increase In Renin Secretion Rate Research Articles

What are the benefits of renal denervation in patients with resistant hypertension?

Systemic arterial hypertension is one of the most important public health issues, affecting more than one-quarter of the adult population in industrialized countries [1]. It is a major risk factor for cardiovascular disease morbidity and mortality [2,3]. In most patients, hypertension can be effectively managed by a combination of lifestyle interventions and medication [4]. However, a significant portion of patients treated for hypertension are resistant to therapy. Conventionally, resistant hypertension is defined as persistent elevation of blood pressure above goal levels despite the use of at least three hypertensive agents from different classes, including a diuretic, in optimal doses [5]. Current prevalence estimates suggest that 10–30% of patients with hypertension may be resistant to drug therapy [6]. Renal sympathetic overactivity seems to play a crucial role in the development of arterial hypertension and resistance to treatment. Activation of efferent renal sympathetic nerve fibers results in an increased renin secretion rate, increased renal vasoconstriction and enhanced sodium and water retention [7]. In addition, afferent sympathetic activation from the kidneys to the CNS, seems to enhance sympathetic nerve discharge itself again, leading to a vicious circle in the development of arterial hypertension and cardiovascular morbidity [8]. Both effects, the activation of efferent renal sympathetic nerve fibers as well as the afferent ‘feedback’ from the kidneys seem to play a crucial role in the pathogenesis and maintenance of arterial hypertension. The idea of treating arterial hypertension by targeting the autonomic nervous system is decades old. In the predrug era, treatment of malignant hypertension was limited to surgical approaches, such as nephrectomy and surgical lysis of the autonomic nerves. Nonselective surgical sympathectomy (thoracolumbar splanchnicectomy), the so-called Smithwick intervention,

CGMP stimulates renin secretion in vivo by inhibiting phosphodiesterase-3

The interaction between renin, nitric oxide (NO), and its second messenger cGMP is controversial. cAMP is the stimulatory second messenger for renin but is degraded by phosphodiesterases (PDEs). We previously reported that increasing endogenous cGMP in rats by inhibiting its breakdown by PDE-5 stimulated renin secretion rate (RSR). This could be reversed by selective inhibition of neuronal nitric oxide synthase (nNOS). PDE-3 metabolizes cAMP, but this can be inhibited by cGMP, suggesting that renal cGMP could stimulate RSR by diminishing PDE-3 degradation of cAMP. Rats were anesthetized with Inactin before determination of blood pressure (BP), renal blood flow (RBF), and sampling of renal venous and arterial blood to determine RSR. In 13 rats, basal BP was 104 +/- 2 mmHg, RBF was 6.1 ml x min(-1) x g kidney wt(-1) and RSR was 2.9 +/- 1.4 ng ANG I x h(-1) x min(-1). Inhibiting PDE-5 with 20 mg/kg body wt i.p. Zaprinast did not change hemodynamic parameters but increased RSR fivefold to 12.2 +/- 4.9 ng ANG I x h(-1) x min(-1) (P < 0.05). Renal venous cAMP was increased by Zaprinast from 93.8 +/- 27.9 to 149.2 +/- 36.0 pM x min(-1) x g kidney wt(-1) (P < 0.05). When another 10 rats were treated with the PDE-3 inhibitor Milrinone (0.4 microg/min over 30 min, which did not affect hemodynamics), RSR was elevated to 10.4 +/- 4.4 ng ANG I x h(-1) x min(-1). Milrinone also increased renal venous cAMP from 212 +/- 29 to 304 +/- 29 pM x min(-1) x g kidney wt(-1) (P < 0.025). Administration of Zaprinast to rats pretreated with Milrinone (n = 10) did not further increase in RSR (7.5 +/- 3.3 ng ANG I x h(-1) x min(-1)). These results are consistent with endogenous renal cGMP inhibiting PDE-3, which diminishes renal metabolism of cAMP. The resulting increase in cAMP serves as an endogenous stimulus for renin secretion. This suggests a pathway by which NO can indirectly stimulate RSR through its second messenger cGMP.

Cardiovascular and Renal Regulation by the Angiotensin Type 2 Receptor

The renin-angiotensin system is a coordinated hormonal cascade of major importance in cardiovascular and renal regulation. The principle effector of this system is the octapeptide angiotensin II (Ang II), which acts at 2 cell membrane receptors, AT1 and AT2. The majority of the actions of Ang II have been demonstrated to be mediated by the AT1 receptor, including growth promotion, vasoconstriction, antinatriuresis, aldosterone secretion, salt appetite, thirst, sympathetic outflow and inhibition of renin biosynthesis, and secretion.1 The AT2 receptor has been less well understood. Past studies, however, clearly demonstrated that the AT2 receptor mediates cellular differentiation and growth, opposing the actions of Ang II through the AT1 receptor.2 Studies in the mid to late 1990s demonstrated that AT2 receptor stimulation engenders an autacoid vasodilator cascade composed of bradykinin (BK), nitric oxide (NO), and guanosine cyclic 3′, 5′-monophosphate (cGMP).3–5 This discovery turned attention to the possibility that the AT2 receptor may mediate vasodilation, opposing the vasoconstrictor actions of Ang II at the AT1 receptor.6 Parallel cell signaling studies indicated that the AT2 receptor is G-protein–coupled (through Giα) and that receptor stimulation is accompanied by an increase in phosphotyrosine phosphatase activity and an inhibition of MAP kinase enzymes (p42 and p44) composing the extracellular signal-related kinase (ERK1/2). AT2 receptor-mediated inhibition of the extracellular signal-regulated kinase pathway opposed the actions of Ang II, resulting in extracellular signal-regulated kinase phosphorylation via the AT1 receptor.1,2,6,7 Work during the late 1990s through 2002 suggested that the AT2 receptor might serve as a vasodilator counterforce to the AT1 receptor.2,6,7 However, vasorelaxation was difficult to elicit in some experimental models, attributed to the relatively low level of AT2 receptor vascular expression compared with that of the …

Mouse gene targeting in cardiovascular physiology.

in the 1980s a revolution took place in cardiovascular physiology unnoticed by many researchers working in the field. At that time, the rat and the dog were the prime animal models to study integrative mechanisms involved in cardiovascular regulation. The notorious but true saying that cells do not

Inhibition of macula densa-stimulated renin secretion by pharmacological blockade of cyclooxygenase-2.

Previous results from our laboratory have shown that in the isolated perfused juxtaglomerular apparatus, nonselective inhibitors of cyclooxygenase (COX) activity prevent the stimulation of renin secretion by a reduction in luminal NaCl concentration at the macula densa. The present studies were performed to examine which COX isoform is involved in NaCl-dependent renin secretion. In the absence of COX inhibitors, a reduction in luminal NaCl (from Na 141/Cl 120 mM to Na 26/Cl 7 mM) caused an increase in renin secretion rate from 4.5 +/- 1.8 to 26.1 +/- 7.4 nGU/min (P < 0.01, n = 19). The presence of the COX-1 inhibitor valerylsalicylate (500 microM) in lumen and bath did not affect the stimulation of renin secretion by a reduction in luminal NaCl concentration (5 +/- 1.8 nGU/min at high NaCl, and 30.5 +/- 9.4 nGU/min at low NaCl; P < 0.01, n = 8). In contrast, the specific COX-2 inhibitor NS-398 (50 microM) in lumen and bath abolished the stimulating effect of low luminal NaCl (12.8 +/- 3.9 nGU/min at high NaCl, and 10.7 +/- 3.1 nGU/min at low NaCl; NS, n = 15). The finding that COX-2 is critically involved in macula densa control of renin secretion indicates that the COX-2-expressing epithelial cells in the tubuloglomerular contact area are a likely source of prostaglandins participating in the signaling pathway between the macula densa and renin-producing granular cells.

The Role of Endogenous Angiotensin II in Antidiuresis and Norepinephrine Overflow Induced by Stimulation of Renal Nerves in Anesthetized Dogs

We examined the possible involvement of endogenous angiotensin II (ANG II) in norepinephrine (NE) overflow and antidiuresis induced by renal nerve stimulation (RNS). RNS at a frequency of 0.5-2.0 Hz, which did not influence renal hemodynamics, produced significant reductions in urine flow and urinary excretion of sodium, and elevations in NE secretion rate (NESR) and renin secretion rate (RSR). Intrarenal arterial (i.r.a.) infusion of phentolamine (10 micrograms/kg/min) abolished the RNS-induced antidiuresis. In dogs receiving captopril (15 micrograms/kg/min i.v.), RNS-induced antidiuresis and increase in NESR were significantly attenuated. The i.r.a. administration of propranolol at 5 micrograms/kg/min, a dose that inhibited completely the RNS-induced increase in RSR, did not influence the alterations in NESR and urine formation in response to RNS. During ANG II infusion (1 ng/kg/min i.r.a.), RNS produced a reduction in urine formation and an increase in NESR, at a magnitude similar to that seen without ANG II infusion. These results suggest that RNS at a low frequency increased the NESR and RSR without affecting renal hemodynamics and that the antidiuretic effect was probably produced via the activation of postsynaptic alpha-adrenoceptors, but not via the ANG II receptor, located on the renal tubules. The release of NE appears to be modulated by ANG II through the activation of a facilitatory prejunctional mechanism, which is maximally stimulated by endogenously and locally generated basal levels of ANG II.

Characterization of the macula densa stimulus for renin secretion

These studies utilize the isolated perfused rabbit juxtaglomerular apparatus (JGA) to study the macula densa signal for renin secretion in the absence of the confounding influences of intravascular pressure and renal nerve activity. In the first experimental series, JGAs were perfused alternately with high- and low-NaCl solutions to determine the reversibility of the renin response to changes in NaCl concentration. Compared with high-NaCl controls, perfusion with a low-NaCl solution resulted in a fivefold increase in renin secretion rate (RSR) [2.1-10.0 nano-Goldblatt hog units (nGU)/min], and this response was largely reversible. When the solutions were presented in the reverse order, a similar inhibition by high NaCl was observed. In the second series, JGAs were perfused with high-, medium-, and low-NaCl solutions to determine the sensitive range of the renin response to NaCl concentration changes. The full renin response (3.2-16.6 nGU/min), similar in magnitude to that seen in series 1, was found to occur between 80 and 24 mM for Na+ and 61 and 7 mM for Cl-. In the third series, the NaCl concentration and flow rate of the perfusate were altered independently to separate the effects of flow rate, NaCl delivery, and NaCl concentration on RSR. Although a decrease in perfusate flow rate slightly increased RSR (3.4-8.1 nGU/min), a comparable decrease in NaCl concentration resulted in a much higher RSR (26.3 nGU/min). We conclude that in this preparation 1) RSR responds equally to both increases and decreases in macula densa NaCl concentration, and these changes are rapid and largely reversible, 2) the full renin response occurs within the concentration range normally occurring at the macula densa, i.e., below 80 mM Na+ and 61 mM Cl-, and 3) RSR responds with a larger change to alterations in NaCl concentration than in NaCl delivery or fluid flow rate.

Role of adrenoceptors in diphenylhydantoin-stimulated renin release.

We have previously shown that diphenylhydantoin (DPH)-stimulated renin release is mediated by, or requires the presence of, the renal nerves. In the present study, we examined the effects of adrenergic blockers in DPH-stimulated renin release in five groups of anesthetized dogs. In vehicle-treated dogs, DPH at a dose of 0.18 mg/kg-min increased renin secretion rate (RSR) from 56 +/- 14 to 269 +/- 60 and returned to 84 +/- 30 ng of angiotensin (ANG) l/hr-min (P less than 0.01, analysis of variance). In metoprolol-treated dogs, DPH produced no significant changes in RSR (90 +/- 28 to 144 +/- 67 to 100 +/- 51 ng of ANG l/hr-min). Likewise, in atenolol-treated dogs, RSR was 34 +/- 10 before, 59 +/- 15 during, and 23 +/- 8 ng of ANG l/hr-min after the infusion of DPH. In contrast, after pretreatment with ICI 118,551 (a beta 2 adrenoceptor antagonist), RSR was 37 +/- 9 before, 151 +/- 57 during, and 47 +/- 12 ng of ANG l/hr-min after the infusion of DPH (P less than 0.01). In phentolamine-treated dogs, RSR was 69 +/- 20 before, 295 +/- 53 during, and 95 +/- 17 ng of ANG l/hr-min after the infusion of DPH (P less than 0.01). Changes in renal blood flow, renal vascular resistance, and UNa V were in the same directions in all groups. These data suggest that DPH-stimulated renin release is mediated by beta 1 adrenoceptors since both beta 2 and alpha adrenoceptor antagonists have no effects on DPH-stimulated renin release.

Renal hemodynamics in response to a kinin analogue antagonist.

The influence of endogenous kinins on renal hemodynamics was studied using a kinin analogue antagonist ([DArg0-Hyp3-Thi5-DPhe7-Thi8]bradykinin) in eight sodium-restricted anesthetized dogs. Clearance periods were run during intrarenal infusion of vehicle or 50 micrograms/min of analogue during normal and reduced renal perfusion pressure within (95 mmHg) and below (65 mmHg) the range of renal autoregulation. During normal renal perfusion, the analogue did not affect arterial pressure, glomerular filtration rate (GFR), or sodium excretion but decreased renal blood flow (RBF) by 20% (6.41 +/- 0.35 vs. 5.61 +/- 0.38 ml.min-1.g kidney wt-1, P less than 0.05) due to increased renal vascular resistance (RVR, 0.44 +/- 0.03 vs. 0.54 +/- 0.04 U, P less than 0.01). The analogue increased renin secretion rate (RSR, 311 +/- 190 vs. 654 +/- 202 ng angiotensin I/min, P less than 0.001). With reduced renal perfusion (95 mmHg), RBF was unchanged, and sodium excretion and RVR decreased. Vehicle did not change GFR, but the analogue abolished autoregulation of GFR (-37%, P less than 0.02) and decreased filtration fraction (24 +/- 4 vs. 34 +/- 4%, P less than 0.05). Renal perfusion pressure of 65 mmHg decreased RBF, GFR, and sodium excretion similarly with vehicle or analogue. Converting-enzyme inhibition eliminated the changes in RVR. Thus kinin antagonism increased RSR and consequently RVR at normal renal perfusion. As renal perfusion pressure decreased, kinin antagonism diminished autoregulation of GFR but not of RBF. These results suggest that kinin antagonism may either modify the arteriolar resistance or alter the coefficient of filtration, resulting in decreased GFR at reduced renal perfusion pressure.

Role of prostaglandin in norepinephrine and renin release in canine kidney.

We investigated renin and norepinephrine (NE) release during electrical renal nerve stimulation (RNS) in relation to prostaglandin (PG) E2 concomitantly produced by the kidney in anesthetized dogs. During 10 min of continuous RNS (2.5-4 Hz), the increases in renin, NE, and PGE2 secretion rates were determined at 1 and 10 min after the start of stimulation. Under control conditions, almost the same extent of increase in the NE secretion rate was observed at 1 and 10 min of RNS, whereas the increase in renin secretion rate at 1 min of RNS was followed by a further increase at 10 min of RNS. On the other hand, an upward but not significant trend of increase in PGE2 secretion at 1 min of RNS was followed by a substantial level at 10 min of RNS. After administration of indomethacin, the increase in NE secretion rates at both 1 and 10 min of RNS were not altered, but the increase in renin secretion rate at 10 min of RNS was suppressed by approximately 50%, without any reduction of the increase in the renin secretion rate at 1 min of RNS. Consequently, the time-related change in the renin secretion rate during RNS was abolished. These results suggest that renin response to continuous RNS is enhanced by concomitantly generated PGs but not by NE, and furthermore, that endogenously generated PGs do not inhibit the release of NE from canine renal nerve endings.

Interaction between epinephrine and renal nerves in control of renin secretion rate.

To determine whether the increase in renin secretion rate (RSR) produced by the beta 2-adrenoceptor agonist epinephrine was dependent on intact renal innervation, epinephrine (10 ng X kg-1 X min-1) was infused bilaterally into an innervated and a denervated kidney (ira) of the same anesthetized dog at spontaneous and reduced renal arterial pressure (decreases RAP, 100 mmHg). Epinephrine ira did not affect mean arterial pressure, renal hemodynamics, or urinary sodium excretion of either kidney. At spontaneous RAP epinephrine ira increased RSR from 633 +/- 134 to 926 +/- 137 ng/min in innervated kidneys but did not change RSR in denervated kidneys. decreases RAP in the presence of epinephrine ira resulted in an increase in RSR from 969 +/- 248 to 2,564 +/- 630 ng/min in innervated kidneys, which was greater than that produced in the absence of epinephrine, from 741 +/- 244 to 1,606 +/- 431 ng/min. In denervated kidneys decreases RAP resulted in similar increases in RSR in the absence and presence of epinephrine ira from 41 +/- 15 to 166 +/- 60 ng/min and from 59 +/- 210 to 235 +/- 78 ng/min, respectively. These results demonstrate that the increase in RSR produced by epinephrine is dependent on intact renal innervation at spontaneous and decreases RAP and suggest that epinephrine increases RSR by a prejunctional mechanism. The beta 1-adrenoceptor antagonist metoprolol (0.3-0.5 microgram X kg-1 X min-1 ira) abolished the enhanced RSR response to decreases RAP produced by epinephrine ira. Similarly, the beta 2-adrenoceptor antagonist ICI 118551 (0.005-0.25 microgram X kg-1 X min-1 ira) abolished the enhanced RSR response to decreases RAP produced by epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurogenic antinatriuresis during development of acute cardiac tamponade.

Renal function was measured during the development of cardiac tamponade in anesthetized dogs. Tamponade was induced by infusion of isotonic saline (37 degrees C) into the pericardial space. Step increases in pericardial fluid volume in 20-ml increments from 0 to 160 ml increased renal efferent nerve activity by a total of 140 +/- 58% of control (from 205 +/- 70 microV/s). Since renal nerve traffic was elevated by pericardial fluid volume infusion prior to any changes in arterial pressure, renal function was determined before and after increasing pericardial pressure (PCP) by approximately 5 and 10 mmHg. Increasing PCP by 5 mmHg decreased urinary sodium excretion and increased renin secretion rate without changing mean arterial pressure, renal blood flow, or glomerular filtration rate (GFR). Further elevation of PCP to approximately 10 mmHg also decreased urinary sodium excretion as well as arterial pressure and GFR. Renal denervation prevented both of these antinatriuretic responses to elevated PCP. In a third group of dogs, similar antinatriuresis was induced by increasing PCP by approximately 5 and 10 mmHg. Bilateral cervical vagotomy abolished the antinatriuretic response to increased PCP by 5 mmHg but was ineffective when PCP was increased by 10 mmHg, which was accompanied by decreased arterial pressure. These results demonstrate that elevation of pericardial fluid volume, and consequently PCP, reflexly decreases urinary sodium excretion via activation of renal sympathetic outflow. Early reflex antinatriuresis results primarily from activation of cardiopulmonary or splanchnic receptors with vagal afferents, whereas, at larger PCP, reflex antinatriuresis may result from hypotension and unloading of high pressure baroreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions among renal nerves, prostaglandins, and renal arterial pressure in the regulation of renin release.

To examine the interactions among the renal nerves, prostaglandins, and renal arterial pressure in the regulation of renin secretion, experiments using low-frequency renal nerve stimulation (LFRNS; supramaximal voltage, 0.5 ms, 0.5 Hz) were performed in anesthetized dogs. LFRNS, which did not affect renal hemodynamics or urinary sodium excretion, increased renin secretion rate before (79 +/- 16 ng/min) but significantly less after renal arterial administration of indomethacin or meclofenamate (26 +/- 7 ng/min). In a separate group of dogs, LFRNS increased both renin secretion rate (266 +/- 139 ng/min) and renal prostaglandin E2 secretion rate (2,080 +/- 635 ng/min). LFRNS does not alter input stimuli to the renal vascular baroreceptor or tubular macula densa receptor mechanisms for renin secretion and represents a direct neural stimulus for renin secretion; this also increases renal prostaglandin E2 secretion rate, which contributes to the increase in renin secretion rate. The renin secretion rate response of innervated and denervated kidneys to reduction in renal arterial pressure to 50 mmHg was examined before and after indomethacin/meclofenamate administration. The observation that indomethacin/meclofenamate decreased but did not abolish the renin secretion rate response to aortic constriction in innervated kidneys suggests the presence of a prostaglandin-independent mechanism that is mediated by an interaction between the renal nerves and the tubular macula densa receptor, as indomethacin/meclofenamate essentially abolished the renin secretion rate response to aortic constriction in denervated kidneys.

Mechanism of effect of dibutyryl cyclic adenosine 3',5'-monophosphate on canine renal renin release.

We evaluated the effect of intrarenal arterial infusion of dibutyryl cyclic AMP on renal renin release. Dibutyryl cyclic AMP (300 micrograms/kg X min) produced significant and reversible increases in renin secretion rate, renal blood flow and urinary Na+ excretion. In the non-filtering kidneys, dibutyryl cyclic AMP increased renin secretion rate and renal blood flow. In indomethacin-treated dogs, dibutyryl cyclic AMP also produced significant and reversible increases in renin secretion rate and renal blood flow but had no effect on Na+ excretion. During infusion of dibutyryl cyclic AMP, infusion of the Ca ionophore A23187 failed to inhibit renin release. These findings suggest that the effect of dibutyryl cyclic AMP on renin release is not mediated by prostaglandins or intracellular Ca and does not involve the macula densa. We conclude that dibutyryl cyclic AMP has a direct effect on the juxtaglomerular cells.

Mechanism of effect of diphenylhydantoin on renal renin release.

This study was undertaken to delineate the mechanism of the effect of diphenylhydantoin (DPH) on renal renin release. DPH at a dose of 0.18 mg X kg-1 X min-1 was infused for 30 min into the renal artery of anesthetized dogs with acute unilateral renal denervation. In the innervated kidney, DPH infusion increased renin secretion rate (RSR) from 189 +/- 54 to 939 +/- 279 ng ANG I X h-1 X min-1. In the contralateral denervated kidneys, RSR did not change. An identical study was done in a second group of dogs in which unilateral renal denervation was done 24 h prior to DPH infusion. In this group, DPH infusion increased RSR from 63 +/- 57 to 643 +/- 180 ng ANG I X h-1 X min-1 in the innervated kidneys. In the contralateral denervated kidneys, RSR did not change. In a separate group of indomethacin-treated nondenervated dogs, intrarenal infusion of DPH increased RSR from 131 +/- 32 to 452 +/- 88 ng ANG I X h-1 X min-1. The percent increase in RSR in the indomethacin-treated dogs was not significantly different from the non-indomethacin-treated dogs. These data suggest that the stimulatory effect of DPH on renin release is mediated by or requires the presence of renal nerves. The step(s) after the renal nerves is (are) not mediated by prostaglandins.

Effects of variations in renal hemodynamics on the time course of renin secretion rate.

The effects of variations in renal hemodynamics on the time course of renin secretion were studied in dogs anesthetized with pentobarbital-chloralose. Hemodynamic changes were induced either locally in kidneys perfused in situ via an extracorporeal circuit (with or without a pump system) or systemically by hemorrhage or nitroprusside infusion. In the autoperfused kidney the reduction of renal perfusion pressure to approximately one-half of the arterial pressure by inflow occlusion caused an increase in renal conductance (renal vasodilation) and an increase in renin secretion rate (RSR). In the pump-perfused kidney, a step increase in renal blood flow (RBF) caused renal vasoconstriction and a decrease in RSR; a step decrease in RBF caused renal vasodilation and an increase in RSR. Following step changes in RBF, the time constant of the alterations of renal conductance was 56.5 s, and the time constant of the RSR responses was 80.1 s. The total time required to reach a steady state for RSR lagged behind that for renal conductance by approximately 5 min. These differences reflect the time needed for the kidney to release renin in response to changes in renal vascular caliber. The results suggest that renin release occurs in response to the autoregulatory dilation of the renal arterioles. When systemic hypotension was induced by nitroprusside infusion, RSR also increased together with the renal conductance. Following hemorrhage, however, RSR increased despite a decrease in renal conductance, reflecting the role of neurohumoral factors in causing renin release in this case. The comparison of renin secretion following different types of hemodynamic alterations serves to elucidate the mechanisms of renin secretion.

Time dependence of mechanisms in the renin response to renal nerve stimulation

The renin release responses to 1 and 5 min of renal nerve stimulation were determined. The left kidneys of α-chlorolose-anesthetized cats were pump perfused with blood while stimulating the decentralized renal nerves at different frequencies (0.5 ms, 10 V). With renal blood flow (RBF) held constant, 1 min of renal nerve stimulation increased renin secretion rate (RSR) at 1.0 (128%), 4.0 (168%) and 12.0 (160%) Hz. After 5 min of stimulation the responses were not different. Propranolol pretreatment prevented the increase in RSR at 1.0 Hz, and resulted in decreased RSR at 4.0 and 12.0 Hz. This response pattern occurred after 1 and 5 min of renal nerve stimulation. When renal perfusion pressure (RPP) was held constant, RSR at 1 min into the stimulation period was similar to that found in the constant RBF group. However, after 5 min the 4.0 Hz and 12.0 Hz responses were significantly greater than the 1 min responses (242% and 508%). Propranolol pretreatment resulted in renin responses after 1 min of stimulation which were similar to the beta-blocked constant RBF group. After 5 min of stimulation at 4.0 and 12.0 Hz RSR was greater than control levels. The results illustrate that renal nerve evoked renin release is time-dependent under constant RPP conditions. The data indicate the presence of 3 mechanisms in these responses. A beta-adrenergic receptor operates at all frequencies to increase renin release. When renal vasoconstriction occurs additional mechanisms are involved. One is inhibitory, independent of renal hemodynamic conditions and rapidly activated. The second is excitatory, occurs only under constant RPP conditions, and is activated slowly.

Interaction of renal beta 1-adrenoceptors and prostaglandins in reflex renin release.

Anesthetized dogs with isolated carotid sinus preparation were used to examine the mechanisms involved in the increase in renin secretion rate produced by carotid baroreceptor reflex renal nerve stimulation (RNS) at constant renal perfusion pressure. Lowering carotid sinus pressure by 41 +/- 5 mmHg for 10 min increased mean arterial pressure and heart rate, caused no or minimal renal hemodynamic changes, decreased urinary sodium excretion, and increased renin secretion rate. Metoprolol, a beta 1-adrenoceptor antagonist, given in the renal artery, did not affect the decrease in urinary sodium excretion but attenuated the increase in renin secretion rate, from 1,764 +/- 525 to 412 +/- 126 ng/min (70 +/- 8%). Indomethacin or meclofenamate, prostaglandin synthesis inhibitors, did not affect the decrease in urinary sodium excretion but attenuated the increase in renin secretion rate, from 1,523 +/- 416 to 866 +/- 413 ng/min (51 +/- 18%). Addition of metoprolol to indomethacin-pretreated dogs attenuated the increase in renin secretion rate from 833 +/- 327 to 94 +/- 60 ng/min (86 +/- 10%). These results indicate that reflex RNS at constant renal perfusion pressure results in an increase in renin secretion rate that is largely mediated by renal beta 1-adrenoceptors and is partly dependent on intact renal prostaglandin synthesis. The beta 1-adrenoceptor-mediated increase in renin secretion rate is independent of and not in series with renal prostaglandins.

Stimulation of renin secretion by alpha-adrenoceptor agonists.

This study was designed to determine whether stimulation of intrarenal alpha-adrenoceptors can increase renin secretion rate (RSR) in the absence of increased renal vascular resistance and to identify the accompanying changes in renal function. Experiments were performed in pentobarbital-anesthetized dogs in which renal perfusion pressure was maintained at approximately 90 mmHg and the infused kidney was acutely denervated. Renal artery infusion of the alpha-adrenoceptor agonist methoxamine (0.5 microgram X kg-1 X min-1 for 30 min) increased RSR from 160 +/- 95 to 1,376 +/- 385 ng ANG I/min (P = 0.01) but did not decrease renal blood flow (RBF); the same dose infused intravenously had no effect on RSR or RBF. Intra-arterial phenylephrine infusion (0.5 microgram X kg-1 X min-1 for 9 min) increased RSR by 500 +/- 157 ng ANG I/min (P less than 0.01) and decreased both inulin clearance (Cin) and urinary sodium excretion (UNaV) by 25% but did not affect RBF. At a lower concentration of phenylephrine (0.2 microgram X kg-1 X min-1 for 9 min), RSR increased by 318 +/- 103 ng ANG I/min (P less than 0.01) and RBF, Cin, and UNaV did not change. The increase in RSR was completely blocked by prazosin but was unaffected by propranolol. In summary, renin secretion can be stimulated by activation of intrarenal alpha-adrenoceptors even in the absence of increased renal vascular resistance.

Stimulation of renin secretion by vasoactive intestinal peptide.

Vasoactive intestinal peptide (VIP) increased plasma renin activity (PRA) in pentobarbital-anesthetized dogs. A 15-min infusion of VIP directly into the renal artery at a dose of 33 ng . kg-1 min-1 increased renin secretion rate from 1,461 +/- 393 to 5,769 +/- 1,794 ng ANG I . ml-1 . 3 h-1 . min-1, and increased PRA from 19.2 +/- 2.3 to 29.2 +/- 4.7 ng ANG I . ml-1 . 3 h-1. Renal blood flow and creatinine clearance were also increased, whereas plasma potassium concentration and diastolic blood pressure decreased. There was no change in sodium or potassium excretion. When administered intravenously, 33 and 13 ng . kg-1 . min-1 VIP increased PRA. A dose of 3.3 ng . kg-1 . min-1 failed to increased PRA when given intravenously but produced a significant increase in PRA from 22.8 +/- 8.1 to 40.5 +/- 19.4 ng ANG I . ml-1 . 3 h-1 when infused into the renal artery. This increase occurred without any change in plasma potassium concentration or blood pressure. Renin secretion was increased by a two- to threefold increase in plasma VIP; comparable increases in plasma VIP have been reported to be produced by various experimental procedures. The data indicate that VIP increases renin secretion. The peptide appears to act directly on the kidney and may act directly on the juxtaglomerular cells.