Gerard Davis

A study of the action of angiotensin II on perfusion through the cortex and papilla of the rat kidney

The effect of angiotensin II on blood pressure and perfusion of blood through the cortex and papilla regions of the kidney was determined in pentobarbitone‐anaesthetized rats which were subjected to laser‐Doppler flowmetry to estimate regional renal haemodynamics. Angiotensin II was infused at 10, 45 and 150 ng (kg body weight‐1 min‐1) which caused dose‐related increases in blood pressure of 3, 12 and 24%, respectively, and decreases in cortical perfusion of 9, 15 and 24%, respectively. Papillary perfusion did not change at any dose of angiotensin II. This pattern and magnitude of responses to angiotensin II in blood pressure, cortical and papillary perfusions was essentially unaffected (a) following blockade of cyclo‐oxygenase activity with indomethacin (1.3 mg kg‐1 plus 2 mg kg‐1 h‐1), (b) during infusion of a bradykinin antagonist, at 1.3 micrograms min‐1, (c) when renal perfusion pressure was regulated at control levels and (d) following Methylene Blue administration to inhibit potential endothelial‐derived relaxing factor production. By contrast, infusion of phenylephrine at 5, 10 and 20 micrograms kg‐1 min‐1 caused dose‐related increases in blood pressure and decreases in both cortical and papillary perfusions reaching some 28, 7 and 17% respectively at the highest dose of phenylephrine used. These results showed that both cortex and papilla were sensitive to vasoconstrictor agents. They are compatible with the suggestion that angiotensin II regulates cortical but not papillary perfusion in the kidney, and that these responses do not depend on prostaglandin, bradykinin, renal perfusion pressure or endothelium‐derived relaxing factor.

Effect of nitrendipine on autoregulation of perfusion in the cortex and papilla of kidneys from Wistar and stroke prone spontaneously hypertensive rats

1 This investigation examined the autoregulatory efficiency of different vascular regions of the normotensive and stroke prone‐spontaneously hypertensive rat (SP‐SHR) kidney and determined how these myogenic responses were dependent upon extracellular calcium. In acute studies, renal autoregulatory blood perfusion curves for cortex and papilla were generated, autoregulatory indices (AIs) calculated as a ratio of the perfusion change divided by the ratio of the pressure difference where zero represents perfect and 1 equates to no autoregulation. The influence of a calcium channel antagonist on this AI was measured at both cortex and papilla. 2 Rats were anaesthetized with sodium pentobarbitone, the kidney exposed and cortical and papillary perfusion measured by Laser‐Doppler flowmetry. Groups of rats either received no drug or nitrendipine at either 0.125 or 0.25 μg kg−1 min−1. 3 In the Wistar normotensive rats there was efficient autoregulation in the cortex (AI = 0.21 ± 0.17), from 127 to 90 mmHg, but not in the papilla (AI = 0.89 ± 0.08), while below 90 mmHg perfusion in both regions decreased with renal perfusion pressure. Nitrendipine attenuated cortical autoregulation at the higher pressure range (AI = 0.62 ± 0.13 and 0.92 ± 0.10 at the low and high dose, respectively) while having no effect on the papillary pressure perfusion pattern. 4 In the SP‐SHR, reduction in renal perfusion pressure, from 150 to 100 mmHg, gave a cortical AI of 0.49 ± 0.10, indicating impaired autoregulation, whereas the papilla demonstrated little myogenic response. Over the high pressure range in the presence of both doses of nitrendipine there was neither cortical (AI of 0.75 ± 0.11 and 0.94 ± 0.12, respectively) nor papillary autoregulation. 5 Autoregulation in the renal cortex but not papilla of the young Wistar rats is well developed. The myogenic responses are attenuated by the calcium channel antagonists suggesting that they are dependent upon the availability of extracellular calcium. Cortical autoregulation in the SP‐SHR is deficient compared to the normotensive rats and is further impaired by the calcium channel antagonists.

Somatosensory regulation of renal function in the stroke-prone spontaneously hypertensive rat.

1. Chloralose‐urethane‐anaesthetized Wistar rats and stroke‐prone spontaneously hypertensive rats (SHRSP) were prepared for measuring renal function. 2. Bilateral brachial nerve stimulation for 15 min, at 1.3 Hz (15 V, 0.2 ms), increased blood pressure from 119 +/‐ 2 to 151 +/‐ 6 mmHg (P < 0.01) in Wistar rats and from 181 +/‐ 6 to 203 +/‐ 6 mmHg (P < 0.05) in SHRSP; renal perfusion pressure was mechanically regulated at prestimulus levels but renal blood flow (4.1 +/‐ 0.7 ml min‐1 g‐1 in Wistar rats and 3.4 +/‐ 0.3 ml min‐1 g‐1 in SHRSP) and glomerular filtration rate (1.18 +/‐ 0.09 ml min‐1 g‐1 in Wistar rats and 0.88 +/‐ 0.01 ml min‐1 g‐1 in SHRSP) decreased between 5 and 30% (P < 0.05‐0.001). 3. During brachial nerve stimulation, urine flow (13.8 +/‐ 2.2 microliters min‐1 g‐1) and absolute and fractional sodium excretion (3.70 +/‐ 0.64 mumol min‐1 g‐1 and 2.06 +/‐ 0.23%) decreased by 60‐70% in the Wistar rats (P < 0.01‐0.001) and the responses were unaffected by vagotomy or carotid sinus denervation. In the SHRSP, urine flow rate (9.74 +/‐ 2.52 microliters min‐1 g‐1) and absolute and fractional sodium excretion (1.98 +/‐ 0.59 mumol min‐1 g‐1 and 1.41 +/‐ 0.28%) decreased by 15‐30% (P < 0.05‐0.01), decreases which were significantly (P < 0.05) smaller than those observed in the Wistar rats. Moreover, the responses were some 40‐60% larger in the vagotomized and carotid sinus‐denervated SHRSP. 4. The influence of vagal and carotid sinus afferent nerves on the somatosensory‐induced renal responses in the Wistar rats was small, whereas in the SHRSP they appeared to exert a marked tonic inhibitory effect. It is concluded that there is excessive baroreceptor restraint on neural regulation of renal function in the SHRSP.

EFFECT OF SOMATIC NERVE STIMULATION ON THE KIDNEY IN INTACT, VAGOTOMIZED AND CAROTID SINUS-DENERVATED RATS

1. The influence of cardiopulmonary and arterial baroreceptors on the renal nerve‐dependent functional responses of the kidney to electrical stimulation of somatic afferent nerves was studied in pentobarbitone‐anaesthetized rats. 2. Electrical stimulation of the left brachial nerve plexus at 3 Hz, 0.2 ms and 15 V in the intact animals increased blood pressure by 22%, and while renal perfusion pressure was maintained at pre‐stimulus levels, renal blood flow and glomerular filtration rate decreased by 14 and 22% respectively. At the same time urine flow rate and absolute and fractional sodium excretion decreased by 36, 42 and 27% respectively. In animals subjected to acute renal nerve section these renal functional responses could not be elicited. 3. Following bilateral vagotomy the systemic and renal haemodynamic responses to brachial nerve stimulation were similar to the intact group. However, urine flow rate and absolute and fractional sodium excretions decreased by 50, 59 and 47% respectively, responses which were significantly greater than in the intact group. 4. In a group of rats in which the carotid sinus nerves had been sectioned, stimulation of the brachial plexus caused reductions of renal blood flow and glomerular filtration rate of the same magnitude as in the intact group; however, urine flow rate and absolute and fractional sodium excretion fell by 51, 60 and 48%, respectively, which were significantly larger than in the intact group. 5. These results demonstrate that the afferent nerve information arising from muscle joints and skin and carried via the brachial plexus caused reflex renal nerve‐dependent reductions in renal haemodynamics and an antidiuresis and antinatriuresis. The cardiopulmonary and carotid sinus baroreceptors exert a tonic inhibitory action on these reflex renal responses insofar as they appeared to attenuate the antidiuretic and antinatriuretic responses to somatic afferent nerve stimulation.

Renal sympathetic nerve responses to somato-sensory nerve stimulation in normotensive rats

Blood pressure, heart rate and renal sympathetic nerve activity were recorded in groups of chloralose/urethane-anaesthetised intact, vagotomised and carotid sinus denervated Wistar rats before and during bilateral somatic afferent nerve stimulation from 0.1 to 3.2 Hz. Renal sympathetic nerve activity was subjected to power spectral and cross correlation analysis. Haemodynamic and integrated renal nerve responses to graded brachial nerve stimulation were not altered by either bilateral vagotomy or carotid sinus denervation and total power of the spectra, from 0-10 Hz, was similar in each group. The percentage power peak at heart rate in intact rats decreased with increasing stimulus frequency, from a control value of 19.2 +/- 1.9% to a minimum of 2.8 +/- 0.7% at 1.6 Hz, while coherence and phase were not altered. Conversely, the peak at the stimulus frequency rose with increasing stimulus frequency reaching 35.3 +/- 2.0% at 3.2 Hz. In the vagotomised group, power at heart rate was significantly lower at each stimulus frequency compared to intact rats although coherence was similar and the phase difference was larger. The peak power at stimulus frequency, coherence and phase difference were similar to those obtained in the intact rats. In the carotid sinus denervated rats, the percentage power at heart rate, coherence and phase difference were significantly smaller than in intact rats. The peak at the stimulus frequency and the phase difference were similar to those obtained in the intact rats whereas coherence was lower. These findings demonstrate that the pattern of renal nerve activity can be changed from one modulated by the baroreceptor to one driven by somatic afferent nerve activity. The vagus appears to play a minor role in the overall pattern of renal nerve activity with the primary controller being the carotid sinus baroreceptors. The data also show that the renal nerve response to somatic afferent nerve stimulation is independent of the afferent nerve input arising from either the atrial or the carotid sinuses.

The effect of angiotensin II and vasopressin on renal haemodynamics.

A comparison was made of the vascular actions of two hormones having a renal site of action, angiotensin II and vasopressin, using laser Doppler flowmetry to measure perfusion of the cortical and papillary regions of the kidney. Angiotensin II infusion caused dose-related increases in blood pressure and reductions in cortical perfusion, the latter responses being potentiated in the presence of the converting enzyme inhibitor, cilazapril. However, angiotensin II had no effect on papillary perfusion either before or following cilazapril. The reasons for this differing vasoconstrictor ability of angiotensin II at the cortex and papilla are unclear, but it could be due to medullary generation of prostaglandin or bradykinin. Administration of equipressor doses of vasopressin caused graded reductions in both cortical and papillary perfusions, and subsequent cilazapril significantly enhanced the papillary responses. This study demonstrates that the regulation of blood flow through the different regions of the kidney can be differentially regulated by the peptide hormones angiotensin II and vasopressin.

Renal nerve responses to somatic nerve activation in stroke-prone spontaneously hypertensive rats

In chloralose/urethane anaesthetised stroke-prone spontaneously hypertensive rats, blood pressure and integrated renal nerve activity were higher whereas heart rate was lower than in Wistar rats by 37, 146 and 11%, respectively (all P < 0.001). The renal nerve signal was subjected to fast Fourier transformation to generate power spectra. In the hypertensive rats, total spectral power was 400% (P < 0.01) and power at the heart rate frequency was 50% (P < 0.01) greater while phase and time differences were shorter (both P < 0.001) than in Wistar rats. Brachial nerve stimulation increased total power in Wistar and hypertensive rats (P < 0.05), but importantly, power at the heart rate frequency was decreased by 80% in Wistar whereas there was a 20% (P < 0.05) increase in hypertensive rats, while phase and time differences were raised only in hypertensive rats (P < 0.05). Bilateral cervical vagotomy of the hypertensive rats had minimal actions on most variables but phase and time differences were doubled compared to intact hypertensive animals, but brachial nerve stimulation decreased power at the heart rate frequency (P < 0.05) which was a very different response from intact rats. Resting blood pressure, heart rate, total power and power at the heart rate frequency in the carotid sinus denervated animals were lower than in intact hypertensive rats, between 17 and 71%, respectively, but increased during brachial nerve stimulation. These experiments demonstrated that whereas somatic sensory input can modulate the pattern of sympathetic nerve activity to the kidney under normal conditions, this does not occur in the hypertensive rat. This appears to be related to afferent information carried by the vagus which suppresses the normal response; the carotid sinus baroreceptors are devoted to organising the nerve activity in relation to the blood pressure pulse wave.

An investigation into the influence of vasopressin on perfusion of the cortex and papilla of the rat kidney

An investigation was undertaken to examine the effects of vasopressin on blood pressure and perfusion of the cortical and papillary regions of the kidney, and to determine the receptor subtype involved. Pentobarbitone‐anaesthetized rats were used and laser‐Doppler flowmetry applied to measure regional renal haemodynamics. Infusion of vasopressin at 10, 20 and 40 mU kg‐1 min‐1 caused dose‐related increases in blood pressure and reductions in cortical and papillary perfusion of approximately 21, 35 and 41%, respectively at the highest dose. Administration of the V1‐receptor antagonist, [1‐(beta‐mercapto‐beta,beta‐cyclopentamethylene propionic acid), 2‐(o‐methyl)tyrosine]‐Arg8‐vasopressin, at 1 microgram kg‐1 plus 5 micrograms kg‐1 h‐1 or four times this dose had no effect on the basal levels of any variable. Vasopressin administration during the low dose of antagonist increased blood pressure and reduced papillary perfusion, the magnitudes of which were only slightly less than those obtained in the absence of the drug, whereas there was a significant attenuation of the response in cortical perfusion. During infusion of the V1 antagonist at 4 micrograms kg‐1 plus 20 micrograms kg‐1 h‐1, vasopressin had no effect on either blood pressure or renal haemodynamics. Infusion of the V2 antagonist, [d(CH2)5, D‐Phe2, Ile4, Arg8, Ala9‐NH2]‐vasopressin at 1 microgram kg‐1 plus 5 micrograms kg‐1 h‐1, and twice this dose had no effect on the basal value of any variable and had no effect on the ability of vasopressin to induce an increase in blood pressure or cause reductions in renal cortical and papillary perfusions. However, the administration of the V2 antagonist at 4 micrograms kg‐1 plus 20 micrograms kg‐1 h‐1 significantly attenuated blood pressure, cortical and papillary perfusion responses to the vasopressin. These studies have shown that vasopressin, given at doses which increased blood pressure, caused dose‐related decreases in perfusion of renal cortex as well as the papilla. The data further show that these systemic and renal actions were mediated primarily by V1‐receptors and that the contribution of V2‐receptors at these vascular beds was very small.

Baroreceptor and somatic sensory regulation of kidney function in two-kidney, one-clip Goldblatt hypertensive rats.

The aim of this investigation was to characterize the renal haemodynamic and tubular responses to somatic afferent nerve stimulation following the removal of afferent nerve input from the atria or the carotid sinuses in chloralose‐urethane‐anaesthetized Sprague‐Dawley rats and two‐kidney, one‐clip Goldblatt hypertensive rats. Bilateral stimulation of the brachial nerve plexi at 15 V, 1.3 Hz for 0.2 ms resulted in an increase in systemic blood pressure in each group of 10‐40%, while renal perfusion pressure was maintained at a constant level. There were significantly larger falls in left renal blood flow and combined left and right glomerular filtration rate in all groups following selective denervation of either the cardiopulmonary or the carotid sinus baroreceptors, respectively. Brachial nerve stimulation decreased urine flow rate and absolute and fractional sodium excretion from both kidneys in Sprague‐Dawley intact animals by 53, 65 and 59%; in vagotomized animals by 68, 77 and 63%; and in carotid sinus denervated animals by 86, 90 and 48%, respectively. The renal response in the Goldblatt group were similar to the normotensive group, but the main contribution of the total response was from the untouched left kidney. The inhibitory influence of the vagus and carotid sinuses on the renal sympathetic nerve‐mediated sodium and water resorption appeared to be enhanced in the Goldblatt hypertensive rats when compared with the normotensive rats. The renal functional responses to somatic afferent nerve stimulation appeared to be well preserved in the renovascular hypertensive rats, although there were important differences in the contributions to the responses from the left and right kidneys. Furthermore, the baroreceptors exerted a greater influence on basal renal function in the hypertensive rats.