The release of renin from the juxtaglomerular granular cells is regulated by three primary mechanisms, a renal vascular baroreceptor, which is sensitive to changes in renal perfusion pressure within the afferent arteriole, a tubular macula densa-mediated process that is sensitive to distal tubular delivery of filtrate, and the renal sympathetic nerves .
Renin-containing granular cells are found within the cytoplasm of modified smooth muscle cells in the afferent arteriole close to the glomeruli. In response to stimulation, the increased renin secretion is due to an increase in the number of renin-expressing and renin-secreting cells and not to more renin being released per granular cell . There is a differential location of the juxtaglomerular granular cells responding to changes in sodium chloride concentration and/or transport and those responding to β-adrenoceptor stimulation, such as the renin-containing cells responding to changes in tubular sodium concentration are located closer to the glomeruli than those responding to activation of β1-adrenoceptors .
Renin secretion is positively regulated by the second messenger cAMP. All agents that activate adenylyl cyclase in juxtaglomerular granular cells will increase renin secretion, including β-adrenoceptor agonists. Neurally induced renin secretion is mediated by norepinephrine-activating β1-adrenoceptors coupled to Gs proteins . The importance of the Gs protein for renin secretion was shown in mice with Gs deficiency in the juxtaglomerular granular cells. These mice were characterized by low basal renin levels and a failure to respond to known stimuli of renin secretion, including furosemide and isoproterenol . The fundamental importance of cAMP in renin secretion is further emphasized by its role in the transcription of renin mRNA . There are a number of reports suggesting that cAMP has a key role in activating the renin gene, and thereby the generation of mRNA, and also contributes to the enhanced stability of the renin mRNA . Thus, activation of cAMP leads to release of renin from the granular cells into the blood stream. Concurrently, the cAMP-mediated activation of PKA leads to phosphorylation of cAMP-responsive element-binding proteins with the eventual result of increased generation of renin protein.
Another intracellular mechanism that regulates renin secretion is Ca++ [15, 223]. In contrast to most secretory cells, renin secretion from the juxtaglomerular granular cells is inversely related to the extracellular and intracellular Ca++ concentrations. The mechanisms involved in the Ca++-mediated suppression of renin secretion involve inhibition of adenylyl cyclase type V and activation of phosphodiesterase, the enzyme responsible for degradation of cAMP activity. Taken together, these effects of Ca++ lead to decreases in the generation of cAMP and the release of renin. It has been suggested that increases in intracellular and extracellular calcium contribute to the decreases in renin secretion produced by various mechanisms, including increased renal perfusion pressure, increased tubular sodium chloride load at the macula densa cells, ANG, and endothelin.
5.1. INCREASES IN EFFERENT RENAL SYMPATHETIC NERVE ACTIVITY
In the rat and mouse kidney, renin gene expression is under tonic influence of the renal sympathetic nerves [110, 111, 264]. Renin mRNA is suppressed in the denervated kidney compared to the contralateral innervated kidney in normal-sodium dietary conditions. Renal renin mRNA levels parallel changes in arterial plasma renin activity. Electrical stimulation of the renal nerves using graded increases in stimulation frequencies results in graded increases in arterial plasma renin activity (PRA) and renal levels of renin mRNA and angiotensinogen mRNA .
Direct electrical and reflex renal sympathetic nerve stimulation results in frequency-dependent increases in both renal venous output of norepinephrine and renin secretion rate [133, 135]. Early studies applied stimulation frequencies that decreased both renal blood flow and urinary sodium excretion making the interpretation of the various mechanisms involved in the neurally mediated release of renin difficult. However in the early 1980s, there were studies showing that renin release could be increased by increases in ERSNA in the absence of changes in renal hemodynamics and urinary sodium excretion if a very low stimulation frequency was applied  (Figure 1.1). Therefore, the resultant increase in renin secretion rate occurred in the absence of changes in the known input stimuli to either the baroreceptor or the macula densa receptor mechanisms, thus demonstrating a direct neural stimulation of renin secretion rate from juxtaglomerular granular cells. Numerous studies have subsequently confirmed these earlier studies. There is now convincing evidence in various species, including man, that supports the view that neurally released norepinephrine acts directly on β1-adrenoceptors located on the juxtaglomerular granular cells to cause renin release [e.g., 133, 201].
A more physiological technique to alter ERSNA is to produce reflex increases or decreases in ERSNA. At normal arterial pressure and blood volume, afferent impulses from the carotid and cardiopulmonary baroreceptors tonically inhibit ERSNA and thereby suppress renin secretion rate [239, 259]. Studies in various species have shown that left atrial distension or acute volume expansion, experimental procedures, which activate cardiopulmonary baroreceptors, inhibit ERSNA and reduce renin secretion rate. The inhibition in renin secretion rate is dependent on intact renal innervation . Conversely, unloading cardiopulmonary baroreceptors by passive head-up tilt in dogs, cats, and humans  or nonhypotensive hemorrhage in dogs  increases renin secretion rate to a greater extent in the innervated than in the denervated kidney.
With respect to the afferent nerves from the carotid baroreceptors, carotid sinus hypotension results in a consistent and significant increase in renin secretion rate only in the presence of vagotomy and constant renal perfusion pressure [45, 119]. The results from these and other studies have clearly shown that there is an interaction among afferent neural input from arterial (carotid, aortic) and cardiopulmonary baroreceptors in the reflex neural control of renin secretion rate. Renin secretion rate increases when there is a decrease in the inhibitory input from any one of the three peripheral baroreceptor stations (carotid, aortic, or cardiopulmonary), if such a withdrawal does not alter the activity of the other two .
5.2. INTERACTION BETWEEN NEURAL AND NON-NEURAL MECHANISMS FOR RENIN SECRETION
Numerous studies demonstrate that basal levels of ERSNA determine the sensitivity of the other two main mechanisms regulating renin secretion, i.e., the renal baroreceptor and macula densa mechanisms. This role of renal sympathetic nerve activity is not fully appreciated. The first studies indicating a role for ERSNA modulating the responsiveness of the non-neural mechanisms showed that furosemide or suprarenal aortic constriction elicited a greater renin secretion rate response in the innervated than in the denervated kidney [230, 231] that was not associated with increases in ERSNA . Studies exploring this issue in more detail showed that renal sympathetic nerve stimulation shifts the stimulus response curve of renin secretion rate on renal perfusion pressure to the right (i.e., to higher renal perfusion pressure)  (Figure 5.1). At high levels of renal perfusion pressure, when there is little to no baroreceptor stimulation, high intensities of renal sympathetic nerve stimulation evoke little increase in renin secretion rate. At low levels of renal perfusion pressure, when there is increasing baroreceptor stimulation, lower intensities of renal sympathetic nerve stimulation are capable of producing large increases in renin secretion rate.
Low-sodium diet also increases the sensitivity of the renin stimulus–response curve, i.e., for the same reduction in renal perfusion pressure, there was an increased renin secretion rate response in sodium-restricted dogs . Whether the enhanced sensitivity was related to increased ERSNA was not examined, but it is known that low-sodium diet (compared with a normal-sodium diet) enhances the increases in plasma norepinephrine concentration produced by decreases in renal perfusion pressure .
In man, similar interaction between ERSNA and non-neural mechanisms in the control of renin secretion rate has been suggested. For example: reflex renal sympathetic nerve stimulation produced by cold pressor stress enhanced the increase in renal venous–arterial difference in plasma renin activity produced by renal arterial pressure reduction . Another study showed that in patients undergoing elective surgery, sympathetic denervation produced by epidural anesthesia abolished both the basal renin secretion rate and the renin secretion rate response to nitroprusside-induced hypotension .
As summarized in further detail by DiBona and Kopp , there is considerable evidence for an interaction between the renal sympathetic nerves and the baroreceptor and macula densa mechanisms in the control of renin secretion rate. ERSNA varies from minute to minute throughout the day. At times, increases in ERSNA sufficient to cause a direct neural release of renin from juxtaglomerular granular cells may occur. Under other circumstances, changes in ERSNA may be more modest but still sufficient to modulate the renin secretion rate responses to stimuli to other mechanisms. The degree of interaction between the neural and non-neural mechanisms is dependent on the level of activation of the non-neural mechanisms and the intensity of renal sympathetic nerve activity. The mechanisms governing this interaction are still unclear.
There is now unequivocal evidence from studies in various species, including man, that the increase in renin secretion rate produced by increases in ERSNA at intensities causing no or minimal changes in renal hemodynamics is mediated by activation of postjunctional β1-adrenoceptors located on juxtaglomerular granular cells [133, 154, 201, 203]. Activation of prejunctional β2-adrenoceptors may also contribute to the increase in renin secretion rate produced by increases in ERSNA. These prejunctional receptors may be increased by circulating epinephrine with a resultant increase in norepinephrine release, which in turn would increase renin secretion rate by activation of postjunctional β1 adrenoceptors .
As discussed above, activation of β1-adrenoceptors, which are G protein-coupled transmembrane receptors, leads to activation of adenylyl cyclase. Activation of adenylyl cyclase results in activation of the cAMP/PKA transduction cascade leading to opening of various ion channels, including large conductance Ca++-sensitive voltage-activated potassium channels (BKCa), which in turn results in membrane hyperpolarization and exocytosis of the renin-containing granules [82, 83].
Whether activation of α-adrenoceptors contributes to the neurally mediated renin secretion is dependent on the level of ERSNA. The increase in renin secretion rate produced by renal sympathetic nerve stimulation at intensities causing marked decreases in urinary sodium excretion and renal blood flow is partly related to activation of vascular and/or tubular α-adrenoceptors [106, 134] (Figure 5.2). Importantly, there is little evidence for α-adrenoceptors in the increase in renin secretion rate produced by renal sympathetic nerve stimulation at intensities causing minimal renal hemodynamic changes.