Effect of hypoxia on vascular responses to the carotid baroreflex.

The effect of systemic hypoxia on the vascular responses to the carotid baroreflex was studied in anesthetized, vagotomized, artificially ventilated dogs. One hindlimb, kidney, gracilis muscle, and paw were perfused at constant flow, and neurograms were obtained from renal sympathetic fibers. Bilateral carotid occlusions were performed while the animal was breathing a mixture of air and O2 (mean arterial PO2 = 106 mmHg) and again during ventilation with 10% O2 (PO2 = 40 mmHg). With occlusion, the average increase in mean aortic pressure was 36 mmHg greater during hypoxia than during normoxia and the increase in renal perfusion pressure was 87 mmHg greater; the increase in hindlimb perfusion pressure was identical in both situations. Hypoxia did not change the reflex response of the paw to carotid occlusion and increased that of the muscle vessels by only 10%; the increase in renal sympathetic activity averaged 56 plus or minus 10% more with hypoxia than with normoxia. When the carotid chemoreceptors were destroyed, the greater increase in aortic and renal pressure response to carotid occlusion during hypoxia as compared to normoxia was abolished. Thus systemic hypoxia markedly potentiates the reflex renal constriction caused by the baroreflex, and this effect is due to the carotid chemoreceptor afferent input.     

Middle cerebral artery blood velocity during rowing

Dynamic exercise increases the transcranial Doppler determined mean blood velocity in basal cerebral arteries corresponding to the cortical representation of the active limb(s) and independent of the concomitant rise in the mean arterial pressure. In 12 rowers we evaluated the middle cerebral artery blood velocity response to ergometer rowing when regulation of the cerebral perfusion is challenged by stroke synchronous fluctuation in arterial pressure. Rowing increased mean cerebral blood velocity (57 ± 3 to 67 ± 5 cm s^?1; mean ± SE) and mean arterial (86 ± 6 to 97 ± 6 mmHg) and central venous pressures (0 ± 2 to 8 ± 2 mmHg; P < 0.05). The force on the oar triggered an averaging procedure that demonstrated stroke synchronous sinusoidal oscillations in the cerebral velocity with a 12 ± 2% amplitude upon the average exercise value. During the catch phase of the stroke, the mean velocity increased to a peak of 88 ± 7 cm s^?1 and it was in phase with the highest mean arterial pressure (125 ± 14 mmHg), while the central venous pressure was highest after the stroke (20 ± 3 mmHg). The results suggest that during rowing cerebral perfusion is influenced significantly by the rapid fluctuations in the perfusion pressure.     

Cardiovascular and endocrine responses to haemorrhage in the pig

Heart rate (HR), mean arterial pressure (MAP), indices of sympathetic and parasympathetic activity (plasma concentrations of adrenaline, noradrenaline and pancreatic polypeptide, PP), vasopressin (VP) and aldosterone (ALDO) were measured in six pigs during continuous bleeding resulting in hypovolaemic shock, from which five survived. Three stages of haemorrhage could be defined. Stage I. Resting MAP was 85 ± 6 mmHg and increased to 96 ± 5 mmHg with a blood loss of 275 (range 250–300) (10 (9–12)% of the estimated blood volume) concomitant with an increase in HR from 105 ± 5 to 113 ± 6 beats min^-1 (P < 0.05). Stage II. After a blood loss of 375 (300–500) ml (15 (13–16)%) MAP fell to 62 ± 9 mmHg and HR to 95 ± 5 beats min^-1 (P < 0.05). Stage III. A blood loss of 1113 (825–1450) ml (44 (30–52)%) resulted in a MAP of 50 ± 4 mmHg and an increase in HR to 206 ± 3 beats min^-1 (P < 0.05). Adrenaline increased from 0.3 ± 0.1 to 0.8 ± 0.3 (stage II) and 3.6 ± 1.1 nmol l^-1 (stage III) (P < 0.05); noradrenaline from 0.4 ± 0.1 to 1.5 ± 0.4 (stage II) and 5.9 ± 1.7 nmol l^-1 (stage III) (P < 0.05); PP from 6.2 ± 1.6 to 13.3 ± 2.3 (stage II) and 20.9 ± 7.8 pmol l^-1 (stage III) (P < 0.05). VP changed only marginally, but ALDO increased from 496 ± 54 to 623 ± 76 pmol l^-1 (stage III) (P < 0.05). The results suggest that a high HR and intense sympathetic activity is seen during severe haemorrhage in the pig while vagal slowing of the heart and moderate hypotension are prominent when bleeding amounts to approximately 15% of the estimated blood volume.     

Renal nerve stimulation restores tubuloglomerular feedback after acute renal denervation

Renal nerves play an important role in the setting of the sensitivity of the tubuloglomerular feedback (TGF) mechanism. We recently reported a time-dependent resetting of TGF to a lower sensitivity 3–4 h after acute unilateral renal denervation (aDNX). This effect persisted after 1 week, but was then less pronounced. To determine whether normal TGF sensitivity could be restored in aDNX kidneys by low-frequency renal nerve stimulation (RNS), the following experiments were performed. Rats with aDNX were prepared for micropuncture. In one experimental group proximal tubular free flow (P_t) and stop flow pressures (P_sf) were measured during RNS at frequencies of 2, 4 and 6 Hz. In another series of experiments the TGF sensitivity was evaluated from the P_sf responses at different loop perfusion rates after 20 min of RNS at a frequency of 2 Hz. The maximal drop in P_sf (ΔP_sf) and the tubular flow rate at which half the maximal response in ΔP_sf was observed (turning point, TP), were recorded. At RNS frequencies of 2, 4 and 6 Hz, P_t decreased from the control level of 14.1 ± 0.8–13.1 ± 1.0, 12.4 ± 1.1 and 11.2 ± 0.8 mmHg (decrease 21%, P < 0.05), respectively, while at zero perfusion and during RNS at 2 and 4 Hz P_sf decreased from 42.5 ± 1.6 to 38.2 ± 1.4 and 32.8 ± 4.3 mmHg (decrease 23%, P < 0.05), respectively. The TGF characteristics were found to be reset from the normal sensitivity with TP of 19.0 ± 1.1 nL min^–1 and ΔP_sf of 8.7 ± 0.9 mmHg to TP of 28.3 ± 2.4 nL min^–1 (increase 49%, P < 0.05) and ΔP_sf of 5.8 ± 1.2 mmHg (decrease 33%) after aDNX. After 20 min of RNS at 2 Hz TP was normalized and ΔP_sf was 33% higher. Thus the present findings indicate that the resetting of the TGF sensitivity that occurred 2–3 h after aDNX could be partially restored by 20 min of RNS at a frequency of 2 Hz. These results imply that renal nerves have an important impact on the setting of the sensitivity of the TGF mechanism.     

Upregulation of the brain renin-angiotensin system in rats with chronic renal failure

Aim: We investigated how the brain renin–angiotensin system is involved in regulation of the sympathetic activity and arterial pressure in rats with chronic renal failure. Methods: Systolic arterial pressure, heart rate and diurnal urinary noradrenaline excretion were measured for 12 weeks in spontaneously hypertensive rats (SHR) with or without subtotal nephrectomy. Expression of mRNAs related to the brain renin–angiotensin system was measured using polymerase chain reaction. Effects of a 6‐day intracerebroventricular infusion of a type 1 angiotensin II receptor antagonist (candesartan) or bilateral dorsal rhizotomy on these variables were also investigated. Results: Systolic arterial pressure and urinary excretion of noradrenaline were consistently higher in subtotally nephrectomized SHR than in sham‐operated SHR (262 ± 5 vs. 220 ± 3 mmHg, P < 0.001; 2.71 ± 0.22 vs. 1.69 ±0.19 ng g^?1 body weight day^?1, P < 0.001). Expression of renin, angiotensin‐converting enzyme and type 1 angiotensin II receptor mRNAs in the hypothalamus and lower brainstem was greater in subtotally nephrectomized SHR than in sham‐operated SHR. Continuous intracerebroventricular infusion of candesartan attenuated hypertension and the increase in urinary noradrenaline excretion in subtotally nephrectomized SHR. Dorsal rhizotomy decreased arterial pressure, urinary excretion of noradrenaline and expression of renin–angiotensin system‐related mRNAs in brains of subtotally nephrectomized SHR. Conclusion: The brain renin–angiotensin system in subtotally nephrectomized SHR appears to be activated via afferent nerves from the remnant kidney, resulting in sympathetic overactivity and hypertension in this chronic renal failure model.     

Angiotensin II and renal prostaglandin release in the dog. Interactions in controlling renal blood flow and glomerular filtration rate

The relationship between angiotensin II and renal prostaglandins, and their interactions in controlling renal blood flow (RBF) and glomerular filtration rate (GFR) were investigated in 18 anaesthetized dogs with acutely denervated kidneys. Intrarenal angiotensin II infusion increased renal PGE₂ release (veno-arterial concentration difference times renal plasma flow) from 1.7 ± 0.9 to 9.1 ±0.4 and 6-keto-PGFja release from 0.1 ±0.1 to 5.3 ± 2.1 pmol min^-1. An angiotensin II induced reduction in RBF of 20% did not measurably change GFR whereas a 30% reduction reduced GFR by 18 ± 8%. Blockade of prostaglandin synthesis approximately doubled the vasocon-strictory action of angiotensin II, and all reductions in RBF were accompanied by parallel reductions in GFR. When prostaglandin release was stimulated by infusion of arachidonic acid (46.8± 13.3 and 15.9± 5.4 pmol min^-1 for PGE₂, and 6-keto-PGFja, respectively), angiotensin II did not change prostaglandin release, but had similar effects on the relationship between RBF and GFR as during control. In an ureteral occlusion model with stopped glomerular filtration measurements of ureteral pressure and intrarenal venous pressure permitted calculations of afferent and efferent vascular resistances. Until RBF was reduced by 25–30% angiotensin II increased both afferent and efferent resistances almost equally, keeping the ureteral pressure constant. At greater reductions in RBF, afferent resistance increased more than the efferent leading to reductions in ureteral pressure. This pattern was not changed by blockade of prostaglandin synthesis indicating no influence of prostaglandins on the distribution of afferent and efferent vascular resistances during angiotensin II infusion. In this ureteral occlusion model glomerular effects of angiotensin II will not be detected, and it might well be that the shift from an effect predominantly on RBF to a combined effect on both RBF and GFR induced by inhibition of prostaglandin synthesis is located to the glomerulus. We therefore postulate that renal prostaglandins attenuate the effects of angiotensin II on glomerular surface area and the filtration barrier, and not on the afferent arterioles as previously suggested.     

Sigmoido-rectal junction reflex: Role in the defecation mechanism

The presence of a sphincter at the rectosigmoid junction (RSJ) is debated. This investigation studies the presence or absence of a sphincter and its possible role in sigmoid colon storage and rectal evacuation. Eighteen healthy volunteers (10 males, 8 females) with a mean age of 36.6 ± 14.8 years (range 21–53) were studied. The pressure response of the sigmoid colon, RSJ, and rectum to sigmoid and rectal distension, respectively, was determined before and after anesthetizing either the sigmoid colon or the rectum. The RSJ length was evaluated by the station pull-through technique. Sigmoid distension with balloon volumes of up to 80.6 ± 4.4 ml of H₂O effected no sigmoid, RSJ, or rectal pressure changes (P > 0.05). At a mean sigmoid distension of 88.6 ± 4.1 ml of H₂O, the sigmoid colon showed a significant pressure increase (P < 0.001), a RSJ pressure decrease (P < 0.05), and insignificant pressure changes in the rectum (P > 0.05); the balloon was dispelled into the rectum. Rectal distension of 94.6 ± 5.8 ml of H₂O produced rectal (P < 0.001) and RSJ (P < 0.05) pressure increases. Distension of the anesthetized sigmoid and rectum did not produce pressure changes in the RSJ (P > 0.05). This study demonstrated a high pressure zone at the RSJ of 3.8 ± 0.7 cm in length. This suggests that the RSJ might act as a functional sphincter. It opens reflexly upon sigmoid contraction, by a reflex we call “rectosigmoid inhibitory reflex,” and closes upon rectal contraction, a reflex we call “rectosigmoid excitatory reflex.” The former allows the stored feces in the sigmoid colon to pass to the rectum, and the latter reflex prevents stool reflux to the sigmoid upon rectal contraction. © 1996 Wiley-Liss, Inc.     

Tissue PH2 measurement for continuous estimation of blood flow changes in rat kidney cortex and medulla

A method is described for estimation of local blood flow changes in the renal cortex and medulla, based on continuous polarographic measurement of tissue pressure of electrochemically generated hydrogen (PH₂). The technique was used in anaesthetized female Wistar rats. The changes in cortical PH₂ were negatively correlated with those in flow velocity in the renal artery (Doppler probe). To evaluate the method, PH₂ responses to a reduction of renal perfusion pressure (RPP) and to angiotensin II were examined. RPP reduction from 130 mmHg to 104 mmHg increased the cortical PH₂ by 3.5% and medullary PH₂ by 6.9% (difference significant at P<0.02). With RPP reduction from 113 mmHg to 76 mmHg the values were 6.9% and 11% respectively (difference significant at P<0.001). Angiotensin II infusion increased cortical PH₂ by 8.7% and medullary PH₂ by 4.1% (difference significant at P<0.005). It is concluded that the method enables continuous estimation of blood flow changes in the renal cortex and medulla.     

Central command increases cardiac output during static exercise in humans

Neural control of the circulation during static two-leg exercise was evaluated in 10 subjects. External compression of the legs was employed to assess muscle mechano-receptor influence by achieving the same intramuscular pressure (80 mmHg) as developed during exercise. The muscle metabo-reflex contribution was assessed by post-exercise muscle ischaemia, and the influence from higher centres in the central nervous system (‘central command’) was taken as the part of the response that could not be accounted for by the two reflex contributions. During static exercise, mean arterial pressure was higher (26±3 mmHg; P<0.01) as compared with leg compression (10±2 mmHg) and with post-exercise muscle ischaemia (11±2 mmHg). Heart rate (25±4 b.p.m.) and cardiac output (0.8±0.3 L min^-1) were increased only during static exercise (P<0.05). Increase in total peripheral resistance were similar during static exercise, post-exercise muscle ischaemia and leg compression. The pressor response to static exercise with a large muscle group was equally attributable to mechanical and metabolic stimulation of afferent nerves; and the two influences were redundant in their effect on total peripheral resistance. In contrast, the influence from central command was directed to the heart with elevation of its rate and minute volume.     

High levels of circulating angiotensin II shift the open-loop baroreflex control of splanchnic sympathetic nerve activity,heart rate and arterial pressure in anesthetized rats

Although an acute arterial pressure (AP) elevation induced by intravenous angiotensin II (ANG II) does not inhibit sympathetic nerve activity (SNA) compared to an equivalent AP elevation induced by phenylephrine, there are conflicting reports as to how circulating ANG II affects the baroreflex control of SNA. Because most studies have estimated the baroreflex function under closed-loop conditions, differences in the rate of input pressure change and the magnitude of pulsatility may have biased the estimation results. We examined the effects of intravenous ANG II (10 μg kg⁻¹ h⁻¹) on the open-loop system characteristics of the carotid sinus baroreflex in anesthetized and vagotomized rats. Carotid sinus pressure (CSP) was raised from 60 to 180 mmHg in increments of 20 mmHg every minute, and steady-state responses in systemic AP, splanchnic SNA and heart rate (HR) were analyzed using a four-parameter logistic function. ANG II significantly increased the minimum values of AP (67.6 ± 4.6 vs. 101.4 ± 10.9 mmHg, P < 0.01), SNA (33.3 ± 5.4 vs. 56.5 ± 11.5%, P < 0.05) and HR (391.1 ± 13.7 vs. 417.4 ± 11.5 beats/min, P < 0.01). ANG II, however, did not attenuate the response range for AP (56.2 ± 7.2 vs. 49.7 ± 6.2 mmHg), SNA (69.6 ± 5.7 vs. 78.9 ± 9.1%) or HR (41.7 ± 5.1 vs. 51.2 ± 3.8 beats/min). The maximum gain was not affected for AP (1.57 ± 0.28 vs. 1.20 ± 0.25), SNA (1.94 ± 0.34 vs. 2.04 ± 0.42%/mmHg) or HR (1.11 ± 0.12 vs. 1.28 ± 0.19 beats min⁻¹ mmHg⁻¹). It is concluded that high levels of circulating ANG II did not attenuate the response range of open-loop carotid sinus baroreflex control for AP, SNA or HR in anesthetized and vagotomized rats.     

In vivo evaluation of the improved MCMS-0102 pacemaker with a rapid pacing mode for induction of experimental heart failure in animals

The MCMS-0102 cardiac pacemaker for rapid ventricular pacing to induce heart failure in animals has been improved in terms of miniaturization and performance. To determine the performance of the new MCMS-0102, six devices were implanted in beagle dogs, and two of these devices were reimplanted for continued pacing in a total of eight beagle dogs. The hearts were paced at 260 beats per minute for 4 weeks (P group: n = 8). The hemodynamic status of the P group was examined and compared with nonpaced dogs (NP group: n = 8). The neurohumoral status of the P group was evaluated before and after rapid pacing. Stable operation of the six devices during rapid pacing was confirmed using the telemetry system. Postmortem examinations revealed features similar to clinical heart failure characterized by massive ascites, pleural effusion, cardiomegaly, and liver congestion in all the paced dogs. Cardiac output was 1.1 ± 0.2 l/min in the NP group and 0.5 ± 0.1 l/min in the P group (P < 0.0001). The left atrial pressure and the central venous pressure of the P group and the NP group were 23 ± 6 versus 6 ± 2 mmHg (P < 0.0001) and 10 ± 3 versus 4 ± 3 mmHg (P < 0.001), respectively. In the paced dogs, plasma renin activity increased from 0.5 ± 0.4 to 8.5 ± 7.4 ng/ml/h (P < 0.05) and atrial natriuretic peptide levels increased from 69 ± 41 to 229 ± 72 pg/ml (P < 0.001). The improved MCMS-0102 was successfully implanted in beagle dogs and it succeeded in inducing the congestive heart failure model.     

The effect of angiotensin AT1 receptor blockade in the brain on the maintenance of blood pressure during haemorrhage in sheep

The effect of systemic or intracerebroventricular (ICV) infusion of the angiotensin AT₁ receptor antagonist losartan on blood pressure during hypotensive haemorrhage was investigated in five conscious sheep. Mean arterial pressure (MAP) was measured during haemorrhage (15 mL kg^?1 body wt). Losartan (1 or 0.33 mg h^?1) was given to sheep by ICV, intravenous or intracarotid administration, beginning 60 min before and continuing during the haemorrhage. During control infusion of ICV artificial cerebrospinal fluid, MAP was maintained until 13.16 ± 0.84 mL kg^?1 blood loss, when a rapid reduction of at least 15 mmHg in arterial pressure occurred (the decompensation phase). ICV infusion of losartan at 1 mg h^?1 caused an early onset of the decompensation phase after only 9.8 ± 0.8 mL kg^{? 1} of blood loss compared with control. Intravenous infusion of losartan (1 mg h^?1) also caused an early onset (P < 0.05) of the decompensation phase at 10.2 ± 1.0 mL kg^?1 blood loss. This dose of losartan inhibited the pressor response to ICV angiotensin II, but not to intravenously administered angiotensin II, indicating that only central AT₁ receptors were blocked. Bilateral carotid arterial administration of losartan at 0.33 mg h^?1 caused an early onset of the decompensation phase during haemorrhage at 11.06 ± 0.91 mL kg^?1 blood loss (P < 0.05), which did not occur when infused by intravenous or ICV routes. The results indicate that an angiotensin AT₁-receptor-mediated mechanism is involved in the maintenance of MAP during haemorrhage in sheep. The locus of this mechanism appears to be the brain.     

Nitric oxide and the role of blood pressure variability to the kidney

Blood pressure variability is buffered by at least two mechanisms: the arterial baroreceptor reflex and nitric oxide (NO). Only recently is the importance of blood pressure variations on cardiovascular control being investigated. Here we report of a study performed in conscious dogs, in which renovascular hypertension was induced. Reduction of renal arterial pressure (RAP) to 85 mmHg for 24 h elicited profound hypertension by 60 mmHg (vs. control: 110 ± 3 mmHg; P < 0.01). This was accompanied by reduced volume and sodium excretion (–48% of control, P < 0.01 and –80% of control, P < 0.01, respectively) and augmented renin release by more than two‐fold (P < 0.01). This intervention was compared with a protocol in which RAP was reduced to the same mean value, however, RAP oscillated by ±10 mmHg at 0.1 Hz. This manoeuvre led to a transient increase in NO₃ excretion in urine (P < 0.01), blunted antidiuresis (–14% of control) as well as antinatriuresis (–40% of control) and attenuated the increased renin release by 30% (P < 0.05). In consequence, the magnitude of blood pressure increase was only half as high as that observed during static reduction of RAP (P < 0.01). It is concluded that blood pressure oscillations to the kidney have a profound influence on water and electrolyte balance and on renin release, which alleviates the onset of Goldblatt hypertension.     

Mechanisms of hypotensive effects of a posture change from seated to supine in humans

The hypothesis tested was that the hydrostatic stimulation of carotid baroreceptors is pivotal to decrease mean arterial pressure at heart level during a posture change from seated to supine. In eight males, the cardiovascular responses to a 15‐min posture change from seated to supine were compared with those of water immersion to the xiphoid process and to the neck, respectively. Left atrial diameter and cardiac output (rebreathing) increased similarly during the posture change and water immersion to the xiphoid process and further so during neck immersion. Mean arterial pressure decreased by 12 ± 2 mmHg during the posture change, by 5 ± 1 mmHg during xiphoid immersion, and was unchanged during neck immersion. Arterial pulse pressure increased by 12 ± 3 mmHg during the posture change (P < 0.05) and less during xiphoid and neck immersion by 7 ± 3 mmHg (P < 0.05). Total peripheral vascular resistance decreased similarly during the posture change and neck immersion and slightly less during xiphoid immersion (P < 0.05). In conclusion, the hydrostatic stimulation of carotid baroreceptors combined with some additional increase in arterial pulse pressure, which also stimulates aortic baroreceptors, accounts for more than half of the hypotensive response at heart level to a posture change from seated to supine.     

ANP gene expression in rat hearts during hypoxia

 It is unclear whether the increase in plasma atrial natriuretic peptide (ANP) concentration during hypoxia is due to direct, hypoxia-induced upregulation of ANP secretion in the heart, or to pressure overload of the right ventricle (RV) following hypoxia-induced pulmonary hypertension. To test the hypothesis that hypoxia leads to an early upregulation of the ANP gene, we examined the influence of acute and prolonged inspiratory hypoxia (6 h, 1 or 3 weeks) on the expression of ANP messenger ribonucleic acid (mRNA) in rat heart and compared the results with the expression of the ANP gene after acute pressure overload induced by experimental coarctation of the main pulmonary artery. As a molecular marker for hypertrophy we determined the ratio of α- and β-myosin gene expression. Hypoxia increased systolic RV pressure from 20.0 ± 1.6 mmHg to 27.8 ± 1.6 mmHg (P < 0.01) and 41.6 ± 2.1 mmHg (P < 0.05) after 1 and 3 weeks hypoxia respectively. The ANP plasma concentration did not change significantly after 6 h or 1 week: 232 ± 21 pg/ml (control), 246 ± 25 pg/ml (6 h), 268 ± 25 pg/ml (1 week), but increased significantly after 3 weeks hypoxia (446.8 ± 99.56 pg/ml; P < 0.05). ANP mRNA levels in different regions of the heart did not change after 6 h or 1 week hypoxia. After 3 weeks hypoxia ANP mRNA had increased 2.7-fold in the RV (P < 0.05), 4.2-fold in the left ventricle (LV, P < 0.05), 3.5-fold in the septum (S, P < 0.05) and about 1.4-fold in the right (n.s.) and left atrium (n.s.). Relative ventricular masses increased significantly only for the RV (190%, P < 0.05) during hypoxia. The β/α-myosin mRNA ratio did not change after 6 h hypoxia but, contrary to ANP gene expression, increased after just 1 week (6.1-fold in RV, 7.8-fold in LV, 6-fold in S; P < 0.05) and was more pronounced in the RV after 3 weeks (9.4-fold in RV, 7.6-fold in LV, 9.1-fold in S; P < 0.05). The increase in the β/α-myosin mRNA ratio in the LV contrasts with a lack of increase in relative ventricular mass. Acute pressure overload in the RV after pulmonary arterial banding significantly increased ANP-mRNA and the β/α-myosin mRNA ratio after 1 day in the RV. In the LV ANP mRNA was unchanged. The delayed upregulation of the ANP gene suggests that hypoxia per se is not a significant stimulus for ANP gene expression in the heart and that hypoxia-induced ANP-gene expression in the heart is regulated predominantly by the increase in RV afterload due to hypoxia-induced increased pulmonary pressure. The upregulation of ANP and β-myosin mRNA in the LV during chronic hypoxia has yet to be elucidated. Received: 5 November 1996 / Received after revision and accepted: 24 January 1997     

Effect of nitric oxide and renal nerves on renomedullary haemodynamics in SHR and Wistar rats,studied with laser Doppler technique

The threshold for activation of the humoral renal antihypertensive system, presumably residing in the renomedullary interstitial cells (RIC), is substantially reset upwards in the spontaneously hypertensive rat (SHR). Depressor reactions, normally elicited by an increased renal perfusion pressure, can be inhibited either by high frequency renal nerve stimulation or blockade of nitric oxide synthesis, i.e. manoeuvres decreasing renal blood flow at this high perfusion pressure. The present study was designed to explore the effects on regional renal haemodynamics of blocking NO synthesis with N-ω-nitro-l-arginine (l-NNA) in chloralose anaesthetized SHR and Wistar rats. Mean arterial blood pressure (MAP), heart rate (HR), renal blood flow (RBF), cortical blood perfusion (CBP) and papillary blood perfusion (PBP) were measured in renally innervated and denervated SHR (S_in=8, S_dn=8) and in Wistar rats (W_in=10, W_dn=10). An innervated non-treated Wistar group served as control (C_in=12). The laser Doppler technique was used to record CBP and PBP. MAP increased in all groups receiving l-NNA while HR, RBF and CBP simultaneously decreased. The relative decreases in RBF were more marked into the two SHR groups than in the corresponding Wistar groups. After l-NNA PBP also decreased in all four groups despite the increased MAP and more so in the S_i group; W_i -19±8 (P<0.05), W_d -17±6 (P=0.07), S_i -50±9 (P<0.01) and S_d-25±9% (P<0.05). We conclude that NO is important for maintaining PBP especially in SHR. The more marked decrease in PBP in the innervated SHR suggests a NO/renal nerve interaction in the control of renomedullary blood flow in SHR. This finding may be of importance for the regulation of the humoral renal depressor mechanism.     

Effects of angiotensin II on arterial pressure,renin and aldosterone during exercise

Summary To evaluate the effect of isotonic exercise on the response to angiotensin II, angiotensin II in saline solution was infused intravenously (7.5 ng · kg⁻¹ · min⁻¹) in seven normal sodium replete male volunteers before, during and after a graded uninterrupted exercise test on the bicycle ergometer until exhaustion. The subjects performed a similar exercise test on another day under randomized conditions when saline solution only was infused. At rest in recumbency angiotensin II infusion increased plasma angiotensin II from 17 to 162 pg · ml⁻¹ (P<0.001). When the tests with and without angiotensin II are compared, the difference in plasma angiotensin II throughout the experiment ranged from 86 to 145 pg · ml⁻¹. The difference in mean intra-arterial pressure averaged 17 mmHg at recumbent rest, 12 mmHg in the sitting position, 9 mmHg at 10% of peak work rate and declined progressively throughout the exercise test to become non-significant at the higher levels of activity. Plasma renin activity rose with increasing levels of activity but angiotensin II significantly reduced the increase. Plasma aldosterone, only measured at rest and at peak exercise, was higher during angiotensin II infusion; the difference in plasma aldosterone was significant at rest, but not at peak exercise. In conclusion, the exercise-induced elevation of angiotensin II does not appear to be an important factor in the increase of blood pressure. It is suggested that the vasodilating mechanisms in the working muscles and the vasoconstricting mechanisms in the non-working vascular beds are powerful and dominant during isotonic exercise and attenuate the opposing or additive vasoconstrictor effects of angiotensin II. The negative feedback effect of angiotensin II on renal renin secretion, however, is not inhibited by exercise.     

Effect of changes in transmural pressure on contraction frequency of the isolated right atrium of the rabbit

Experiments were made on preparations of the rabbit right atrium maintained at 37 °C in oxygenated Krebs–Henseleit solution. Baseline diastolic transmural pressure was held at 2 mmHg. A step increase in diastolic pressure was accompanied by an immediate and rapid increase in atrial rate (fast response), followed by a slower increase (t_1/2～0.5 min) (slow response). The slow response to pressure steps was graded, approaching a maximum increase after a 12 mmHg step (44±4 min^-1 from a baseline of 196±5 min^-1; mean±SEM; n=7; P<0.01). In preparations where baseline atrial rate had been reduced 50% by application of carbamylcholine, the slow response to an increase in pressure was augmented (n=7; P<0.01); an increase of 55±9 min^-1 for a 12 mmHg step in atrial pressure. In preparations where baseline rate had been increased 63% by the application of isoprenaline, the slow response was attenuated (n=5, P< 0.01), an increase of 22±7 min^-1 for a 12 mmHg step. During sinusoidal pressure forcing (0.002–1.0 Hz), rate responses of control and carbamylcholine-treated preparations had a high gain at frequencies 0.02 Hz. Carbamylcholine-treated preparations also showed a high gain at frequencies 0.2 Hz. There appear to be two distinct intrinsic responses to changes in right atrial pressure; a rapid response which is augmented by cholinergic stimulation, and a slower response which is augmented by cholinergic stimulation and reduced by β-adrenergic stimulation.     

Tolerance to haemorrhage during vasopressin antagonism and/or captopril treatment in conscious sheep

The effect of separate and combined blockade of vasopressin (AVP) V₁-receptors and angiotensin II formation on resistance to a slow venous haemorrhage (0.7 ml kg^-1 min^-1) was studied in six conscious adult sheep by bleeding to the point of an abrupt fall in the mean systemic arterial pressure (MSAP). Intravenous administration of the V₁-receptor antagonist [d(CH₂)₅Tyr(Me)AVP] (10 μg kg^-1) and/or the angiotensin I converting enzyme inhibitor captopril (20 mg+1 mg h^-1) did not cause any significant haemodynamic changes in the normovolaemic animal. The volume of haemorrhage necessary to induce acute hypotension (MSAP < 50 mmHg) was significantly smaller after AVP blockade alone (13.8±0.7 ml kg^-1; P < 0.01) but not after captopril treatment (14.7±1.6 ml kg^-1; n.s.) compared to control animals receiving no drug treatment (16.8±0.6 ml kg^-1). The combined treatment with the AVP antagonist and captopril caused a further decrease in tolerance to haemorrhage (9.4±1.2 ml kg^-1; P < 0.001). Blockade of AVP V₁-receptors was associated with an attenuated increase in systemic vascular resistance immediately after the end of haemorrhage, concomitant with an accentuated lowering of the central venous pressure. In contrast, captopril treatment decreased the degree of vasoconstriction mainly during the second half of the post-haemorrhage observation period of 1 hour. It is concluded that both AVP and angiotensin II contribute to the maintenance of the MSAP during haemorrhage in conscious sheep. During the spontaneous recovery after hypotensive blood loss, a vasoconstrictor effect of AVP is evident mainly during the initial 15 min, whereas at later stages angiotensin II appears to be of relatively greater importance.     

Renal response to volume depletion and expansion in Milan hypertensive rats

In previous studies on Milan hypertensive (MHS) rats, we found an impaired tubuloglomerular feedback (TGF) response before, during and after development of hypertension. In the present study MHS rats and rats of the Milan normotensive strain (MNS) were investigated after 24 hours of volume depletion (VD) and subsequently after 5% isotonic volume expansion (VE) with respect to whole kidney function, interstitial hydrostatic (P_int) and oncotic (II_int) pressures, stop-flow pressure characteristics of TGF and changes in early proximal flow rate in response to increased loop of Henle flow. MHS rats had higher mean arterial blood pressure (P_a) than MNS rats (129 vs. 101 mmHg) both after VD and after subsequent VE. No difference in glomerular filtration rate (GFR) was found. Both strains had a low urine flow rate (1.5 μl min^-1) during VD, which increased fourfold after VE. The interstitium was significantly more dehydrated in MHS, as indicated by a more negative net interstitial pressure (P_int–±_int t than in MNS (-1.3 ± 0.3 vs. ± 0.0 ± 0.5 mmHg) after VE. The TGF mechanism was more activated in MHS during volume depletion, as indicated by a larger drop in stop-flow pressure (P_sf) in response to loop of Henle perfusion (7.1 ± 0.7 vs. 4.7 ± 0.2 mmHg, P < 0.05). However, during VD the loop of Henle flow that elicited half maximal response in P_sf, the turning point (TP), was equally low in MHS and MNS (13.5 ± 0.6 and 14.3 ± 0.4, respectively). After VE, however, TP increased significantly more in MNS to (32.6 ± 2.1 nl min^-1) then in MHS (to 21.8 ± 0.9 nl min^-1, P < 0.05). It is concluded that the blunting of the TGF resetting in response to VE in MHS rats may well be of importance in the development of hypertension in the MHS strain.