Impairment of the inhibitory renorenal reflexes in pathological conditions of increased ERSNA and sodium retention would aggravate and/or contribute to further increases in ERSNA and sodium retention. There is now considerable evidence for impaired responsiveness of the afferent renal mechanosensory nerves involved in the inhibitory renorenal reflexes in various pathological conditions, including congestive heart failure [146], spontaneous hypertension [137, 161], and diabetes [38, 151]. Likewise, numerous studies by Chen and coworkers [39, 177–179] have presented evidence for reduced natriuretic responses to saline volume expansion in ischemia-induced acute renal failure, obstructive nephropathy, cirrhosis, and hypoxia. The impaired natriuretic responses to acute saline volume expansion are associated with reduced increases in ARNA and decreases in ERSNA, suggesting an impairment of the inhibitory renorenal reflexes. This notion was subsequently confirmed by showing impaired ARNA responses and reduced renal pelvic release of substance P and/or activation of NK1 receptors in response to standardized increases in renal pelvic pressure.

The reduced responsiveness of the afferent renal mechanosensory nerves is related to a suppression of the PGE₂-mediated release of substance P from the afferent renal sensory nerve endings [137, 145, 146, 151]. Rats with heart failure, hypertension, and diabetes are characterized by increased activity of the renin–angiotensin system [58]. A role for ANG II in the reduced responsiveness of the afferent renal mechanosensory nerves in these rats with various pathological conditions was shown by the marked improvement in the responsiveness of the mechanosensory nerves by renal pelvic administration of losartan [141, 146, 151]. Studies in renal pelvises from SHR showed that the reduced PGE₂-mediated release of substance P is, at least in part, related to ANG II activating a pertussis toxin-sensitive mechanism [137]. Taken together, these studies suggest that the reduced responsiveness of afferent renal mechanosensory nerves in rats with congestive heart failure, hypertension, and diabetes may contribute to the increased ERSNA and sodium retention prevalent in these pathological models [58]. Furthermore, the marked enhancement of the renorenal reflex mechanism produced by AT1 receptor antagonists may contribute to the well-known beneficial effects of inhibiting the renin–angiotensin system in heart failure and hypertension.

In addition to the impaired responsiveness of the renal mechanosensory nerves in SHR, the interaction between ERSNA and ARNA is also impaired. The impaired interaction between ERSNA and ARNA is related to increased activation of renal pelvic α₂-adrenoceptors, in addition to increased activation of AT1 receptors [145], i.e., similar mechanisms as those contributing to the suppressed responsiveness of the renal sensory nerves in low sodium diet rats.

Taken together, these studies would suggest an impairment of the inhibitory renorenal reflexes in many pathological models of increased activity of the renin–angiotensin system. An impairment of the inhibitory renorenal reflexes would contribute to the increased ERSNA observed in many of these pathological conditions. In addition, when the inhibitory renorenal reflexes are impaired, excitatory reflexes originating from a diseased kidney may dominate (vide infra).

Studies in two-kidney one-clip rats showed that increasing renal pelvic pressure in the clipped kidney failed to elicit a contralateral renorenal reflex response [136]. Renal denervation of the clipped kidney increased urinary sodium excretion from both the clipped and the contralateral non-clipped kidney. The contralateral natriuretic response was associated with decreases in contralateral ERSNA. These data suggest that the afferent renal nerves in the ischemic kidney exert an excitatory influence on the sympathetic nervous system in contrast to the inhibitory reflexes originating from normal healthy kidneys [43, 60]. Chronic studies by Katholi's group [123, 125] in renovascular hypertensive rats confirmed the excitatory influence deriving from ischemic kidneys. Whereas denervation of the clipped kidney reduced arterial pressure almost to the same level as removing the clip from the renal artery, denervation of the contralateral non-clipped kidney had no effect on arterial pressure. Further studies by this group suggested an important role for adenosine in the excitatory reflexes originating in the ischemic kidneys. Intrarenal administration of adenosine deaminase reduced arterial pressure in one-kidney one-clip hypertensive rats but had no effect in healthy normal rats. Also, administration of adenosine into one renal artery resulted in increases in ERSNA and arterial pressure, which were abolished by renal denervation [124]. Taken together, these studies suggest that excitatory reflexes originating in ischemic kidneys involve adenosine activating chemosensitive afferent renal nerves.

Further evidence for excitatory reflexes originating in diseased/injured kidneys is derived from studies in human and rats with renal failure. Comparing arterial blood pressure and muscle sympathetic nerve activity in hemodialysis patients with and without their native diseased kidneys intact showed markedly reduced arterial pressure and muscle sympathetic nerve activity in patients with bilateral nephrectomy compared to the patients who had their kidneys intact [44]. These findings were subsequently confirmed and extended in studies comparing arterial pressure and muscle sympathetic nerve activity in patients with kidney transplants with and without their native kidneys intact [101]. None of the patients were uremic; thus, they all had well-functioning renal grafts. However, muscle sympathetic nerve activity was increased in all patients vs healthy controls, except in the patients in which bilateral nephrectomy had been performed. In a subgroup of transplant patients, muscle sympathetic nerve activity was measured before and after the second kidney was removed and was found to be reduced following removal of the second diseased kidney. Thus, these studies provide strong evidence for the diseased kidneys exerting an excitatory effect on sympathetic nerve activity. Studies in rats with chronic renal failure would support the notion that the excitatory effects exerted by the diseased kidneys are related to the afferent renal nerves in the diseased/injured kidney exerting an excitatory effect on the sympathetic nervous system [32]. These rat studies showed that chronic renal failure increased arterial pressure and norepinephrine turnover in posterior hypothalamus and locus coeruleus. Importantly, prior dorsal rhizotomy to remove the afferent renal innervation prevented the increases in arterial pressure and norepinephrine turnover in the various brain regions produced by renal failure.

Thus, local renal injury may result in a sympathoexcitatory reflex involving afferent renal nerves, central cardiovascular regulatory areas, and efferent systemic and renal sympathetic nerve activity eventually leading to hypertension.

Although there is evidence for an important renal component in the hypertensive process following renal injury, the mediator(s) at the level of the afferent renal sensory nerve terminal are not known. Studies by Katholi et al. [123–125] would suggest an important role for adenosine-activating chemosensitive nerve fibers in the injured/diseased kidneys resulting in excitatory reflexes. There are also data which show that i.v. cyclosporine increases arterial pressure, at least in part, by activation of the afferent renal nerves. The increase in ARNA and arterial pressure produced by cyclosporine, a calcineurin inhibitor, was not seen in synapsin-deficient mice. These data suggest that the mechanisms causing the sustained increase in ARNA, produced by acute i.v. infusion of cyclosporine, involve alterations in synapsin phosphorylation–dephosphorylation in afferent renal sensory nerve terminals [263]. The important role of synapsin in the cyclosporine-induced activation of ARNA appears to be unique for cyclosporine because capsaicin, which activates sensory nerves by releasing substance P and/or CGRP, produced similar increases in ARNA in wild-type and synapsin-deficient mice.