Long-term Regulation Of Arterial Pressure Research Articles

Renal Medulla in Hypertension.

Studies have found that blood flow to the renal medulla is an important determinant of pressure-natriuresis and the long-term regulation of arterial pressure. First, a brief review of methods developed enabling the study of the medullary circulation is presented. Second, studies performed in rats are presented showing medullary blood flow plays a vital role in the pressure-natriuresis relationship and thereby in hypertension. Third, it is shown that chronic reduction of medullary blood flow results in hypertension and that enhancement of medullary blood flow reduces hypertension hereditary models of both salt-sensitive rats and salt-resistant forms of hypertension. The key role that medullary nitric oxide production plays in protecting this region from ischemic injury associated with circulating vasoconstrictor agents and reactive oxygen species is presented. The studies cited are largely the work of my students, research fellows, and colleagues with whom I have performed these studies dating from the late 1980s to more recent years.

Potential role of intermittent functioning of baroreflexes in the etiology of hypertension in spontaneously hypertensive rats.

The spontaneously hypertensive rat (SHR) is a genetic model of primary hypertension with an etiology that includes sympathetic overdrive. To elucidate the neurogenic mechanisms underlying the pathophysiology of this model, we analyzed the dynamic baroreflex response to spontaneous fluctuations in arterial pressure in conscious SHRs, as well as in the Wistar-Kyoto (WKY), the Dahl salt-sensitive, the Dahl salt-resistant, and the Sprague-Dawley rat. Observations revealed the existence of long intermittent periods (lasting up to several minutes) of engagement and disengagement of baroreflex control of heart rate. Analysis of these intermittent periods revealed a predictive relationship between increased mean arterial pressure and progressive baroreflex disengagement that was present in the SHR and WKY strains but absent in others. This relationship yielded the hypothesis that a lower proportion of engagement versus disengagement of the baroreflex in SHR compared with WKY contributes to the hypertension (or increased blood pressure) in SHR compared with WKY. Results of experiments using sinoaortic baroreceptor denervation were consistent with the hypothesis that dysfunction of the baroreflex contributes to the etiology of hypertension in the SHR. Thus, this study provides experimental evidence for the roles of the baroreflex in long-term arterial pressure regulation and in the etiology of primary hypertension in this animal model.

Logical Issues With the Pressure Natriuresis Theory of Chronic Hypertension.

The term "abnormal pressure natriuresis" refers to a subnormal effect of a given level of blood pressure (BP) on sodium excretion. It is widely believed that abnormal pressure natriuresis causes an initial increase in BP to be sustained. We refer to this view as the "pressure natriuresis theory of chronic hypertension." The proponents of the theory contend that all forms of chronic hypertension are sustained by abnormal pressure natriuresis, irrespective of how hypertension is initiated. This theory would appear to follow from "the three laws of long-term arterial pressure regulation" stated by Guyton and Coleman more than 3 decades ago. These "laws" articulate the concept that for a given level of salt intake, the relationship between arterial pressure and sodium excretion determines the chronic level of BP. Here, we review and examine the recent assertion by Beard that these "laws" of long-term BP control amount to nothing more than a series of tautologies. Our analysis supports Beard's assertion, and also indicates that contemporary investigators often use tautological reasoning in support of the pressure natriuresis theory of chronic hypertension. Although the theory itself is not a tautology, it does not appear to be testable because it holds that abnormal pressure natriuresis causes salt-induced hypertension to be sustained through abnormal increases in cardiac output that are too small to be detected.

A computational analysis of the long-term regulation of arterial pressure

The asserted dominant role of the kidneys in the chronic regulation of blood pressure and in the etiology of hypertension has been debated since the 1970s. At the center of the theory is the observation that the acute relationships between arterial pressure and urine production—the acute pressure-diuresis and pressure-natriuresis curves—physiologically adapt to perturbations in pressure and/or changes in the rate of salt and volume intake. These adaptations, modulated by various interacting neurohumoral mechanisms, result in chronic relationships between water and salt excretion and pressure that are much steeper than the acute relationships. While the view that renal function is the dominant controller of arterial pressure has been supported by computer models of the cardiovascular system known as the “Guyton-Coleman model”, no unambiguous description of a computer model capturing chronic adaptation of acute renal function in blood pressure control has been presented. Here, such a model is developed with the goals of: 1. representing the relevant mechanisms in an identifiable mathematical model; 2. identifying model parameters using appropriate data; 3. validating model predictions in comparison to data; and 4. probing hypotheses regarding the long-term control of arterial pressure and the etiology of primary hypertension. The developed model reveals: long-term control of arterial blood pressure is primarily through the baroreflex arc and the renin-angiotensin system; and arterial stiffening provides a sufficient explanation for the etiology of primary hypertension associated with ageing. Furthermore, the model provides the first consistent explanation of the physiological response to chronic stimulation of the baroreflex.

A computational analysis of the long-term regulation of arterial pressure

The asserted dominant role of the kidneys in the chronic regulation of blood pressure and in the etiology of hypertension has been debated since the 1970s. At the center of the theory is the observation that the acute relationships between arterial pressure and urine production—the acute pressure-diuresis and pressure-natriuresis curves—physiologically adapt to perturbations in pressure and/or changes in the rate of salt and volume intake. These adaptations, modulated by various interacting neurohumoral mechanisms, result in chronic relationships between water and salt excretion and pressure that are much steeper than the acute relationships. While the view that renal function is the dominant controller of arterial pressure has been supported by computer models of the cardiovascular system known as the “Guyton-Coleman model”, no unambiguous description of a computer model capturing chronic adaptation of acute renal function in blood pressure control has been presented. Here, such a model is developed with the goals of: 1. capturing the relevant mechanisms in an identifiable mathematical model; 2. identifying model parameters using appropriate data; 3. validating model predictions in comparison to data; and 4. probing hypotheses regarding the long-term control of arterial pressure and the etiology of primary hypertension. The developed model reveals: long-term control of arterial blood pressure is primarily through the baroreflex arc and the renin-angiotensin system; and arterial stiffening provides a sufficient explanation for the etiology of primary hypertension associated with ageing. Furthermore, the model provides the first consistent explanation of the physiological response to chronic stimulation of the baroreflex.

NTS AT1a receptor on long-term arterial pressure regulation: putative mechanism

This editorial refers to ‘Cardiovascular role of angiotensin type1A receptors in the nucleus of the solitary tract of mice’ by B. Abegaz et al. , pp. 181–191, this issue. Studies over the last 50 years have demonstrated the major role of the central nervous system and renin–angiotensin system (RAS) acting together to control cardiovascular haemodynamic and blood fluid homoeostasis. It is well accepted that the combination of CNS and RAS is the major regulator of blood pressure in both normal and patho-physiological conditions. Considered one of the most important nuclei of the brain stem, the nucleus of the solitary tract (NTS), located at the dorsal brainstem, is the first synaptic relay station in the CNS for cardiovascular and respiratory afferent fibres, among other afferents,1 and contributes in mediating the hypertension and sympathoexcitation observed in spontaneously hypertensive rats.1–3 Most of the classical actions of central Ang II are exerted via the angiotensin II (Ang II) type 1 (AT1) receptor,4 which activates …

Counterpoint: Activation of the Intrarenal Renin-Angiotensin System is the Dominant Contributor to Systemic Hypertension

Our discussion regarding the dominant mechanism responsible for hypertension calls to mind the famous poem, “The Blind Men and the Elephant,” by John Godfrey Saxe based on an ancient fable from India. In essence, the blind men described the elephant based on their specific encounter, thus

The 62nd Annual Fall Conference and Scientific Session of the American Heart Association Council for High Blood Pressure Research in Association With the Council on the Kidney in Cardiovascular Disease

This supplemental issue of Hypertension contains selected articles based on presentations at the 62nd Annual Fall Conference and Scientific Sessions of the American Heart Association Council for High Blood Pressure Research (CHBPR), held September 17 to 20, 2008, in Atlanta, Georgia. The meeting was cosponsored by the Council on Kidney in Cardiovascular Disease (CKCD). The conference was a huge success, with attendees from around the world. The program committee and Drs Gabriel Navar, Chair of the CHBPR, and Jeff Sands, Chair of CKCD, are to be congratulated. The council meeting was preceded by a workshop on “Novel Signaling Paradigms in Vascular and Renal Disease.” Drs Nancy Kanagy and Mathias Barton organized the workshop, and more than 250 individuals attended. The workshop ended with a presentation by Dr Paul Vanhoutte titled, “The Past, Present and Future of Signaling in the Vascular Wall.” Dr Vanhoutte’s talk also opened the fall conference. There were 727 registered attendees at the main council meeting, and 423 abstracts were selected for presentation as oral and poster communications. In addition to the free communications, presentations by award recipients contributed to an excellent meeting. The awards presented at the meeting recognized outstanding achievement in hypertension research. The premier award of the CHBPR, given to investigators who have made outstanding discoveries in hypertension research, is the Novartis Award for Hypertension Research. The recipients of the 2008 Novartis Award were Drs Mordecai P. Blaustein, John W. Funder, and J. Carlos Romero (Figure 1). Dr Blaustein, Professor of Physiology and Medicine at the University of Maryland, was honored for his pioneering discoveries on the sodium-calcium exchanger and its role in the increased vascular tone characteristic of hypertension. Dr Funder, Professor of Medicine at Monash University and Senior Fellow at Prince Henry’s Institute of Medical Research, was honored for his seminal studies …

Sympathetic Activity, Vascular Capacitance, and Long-Term Regulation of Arterial Pressure

I am honored to have been chosen to present the 2008 Arthur C. Corcoran Memorial Lecture, because Dr Corcoran was both a brilliant scientist and one of the founding fathers in the field of hypertension research, but I am particularly gratified to join the list of superb scientists who have preceded me as Corcoran lecturers. When I began studying hypertension as a postdoctoral fellow, under the tutelage of Dr Michael Brody at the University of Iowa, I quickly acquired what turned out to be a lifelong interest in the integrative aspects of cardiovascular system regulation. Because of Dr Brody’s research interests, this naturally included a focus on the sympathetic nervous system. However, a major stimulus for my fascination with integrative physiology was the excitement at that time over the detailed and refined mathematical model of the circulation developed by Arthur Guyton, Thomas Coleman, and colleagues at the University of Mississippi.1 It is well known of course that the model highlights the importance of body fluid volume regulation as the key determinant of long-term arterial pressure regulation. The combined impact of these 2 influences—at a formative stage in my research career—led to my deep interest in the following question: “Can the sympathetic nervous system participate in long-term arterial pressure regulation within the framework of the Guyton-Coleman circulatory model?” Guyton and colleagues incorporated sympathetic regulation into their model. They emphasized the importance of nonrenal sympathetic activity in determining the hemodynamic pattern of many forms of hypertension and the potential for renal sympathetic nerve activity to affect the renal function curve (pressure-natriuresis relationship) and to thereby help establish the long-term value of arterial pressure. However, they also pointed out the tendency of reflex mechanisms regulating sympathetic activity to reset and, thus, maintain sympathetic activity at normal levels. This would minimize the influence …

Effect of stellate ganglionectomy (SGx) on the long‐term responses of arterial pressure (AP) and heart rate (HR) to beta‐1 adrenergic blockade in conscious rats

Alterations in cardiac sympathetic outflow and norepinephrine reuptake are associated with many diseases, including hypertension. However, relatively little is known about the direct role of cardiac sympathetic innervation on regulation of cardiovascular function in conscious animals. Therefore, we examined the effect of chronic denervation of the heart by SGx on regulation of AP and HR in conscious rats. Rats were instrumented for telemetric measurement of AP and HR. After 5 control days, rats were subjected to SGx (N = 9) or SHAM (N = 8) surgery. 7 days later both groups were administered the beta‐1 adrenergic antagonist, atenolol, for 5 days. AP (mmHg) was nearly identical in both groups during the entire protocol including control (SGx; 99 ± 1, SHAM; 98 ± 1), Day 6 after SGx (95 ± 1) or Sham (96± 2), and Day 5 of atenolol (SGx; 90 ± 1, SHAM; 88 ± 1). HR (beats/min) was similar in both groups during control (SGx; 402 ± 6, SHAM; 393 ± 7) but significantly lower 6 days after SGx (337 ± 4) compared to Sham (369 ± 9). By Day 5 of atenolol HR was similar in SGx (308 ± 4) and Sham (310 ± 11) rats. Measurement of tissue norepinephrine (NE) content at the end of the study showed negligible levels of NE in all 4 cardiac chambers of SGx compared to Sham hearts. We conclude that; 1) SGx decreases basal HR but has negligible effects on long‐term regulation of AP and 2) the hypotensive response to atenolol is not mediated by its actions on the heart in normal rats. Supported by NIH Grant HL064178.

Renal Denervation Does Not Abolish Sustained Baroreflex-Mediated Reductions in Arterial Pressure

Recent studies indicate that suppression of renal sympathetic nerve activity and attendant increments in renal excretory function are sustained baroreflex-mediated responses in hypertensive animals. Given the central role of the kidneys in long-term regulation of arterial pressure, we hypothesized that the chronic blood pressure-lowering effects of the baroreflex are critically dependent on intact renal innervation. This hypothesis was tested in 6 dogs by bilaterally activating the carotid baroreflex electrically for 7 days before and after bilateral renal denervation. Before renal denervation, control values for mean arterial pressure and plasma norepinephrine concentration were 95+/-2 mm Hg and 96+/-12 pg/mL, respectively. During day 1 of baroreflex activation, mean arterial pressure decreased 13+/-1 mm Hg, and there was modest sodium retention. Daily sodium balance was subsequently restored, but reductions in mean arterial pressure were sustained throughout the 7 days of baroreflex activation. Activation of the baroreflex was associated with sustained decreases in plasma norepinephrine concentration ( approximately 50%) and plasma renin activity (30% to 40%). All of the values returned to control levels during a 7-day recovery period. Two weeks after renal denervation, control values for mean arterial pressure, plasma norepinephrine concentration, plasma renin activity, and sodium excretion were comparable to those measured when the renal nerves were intact. Moreover, after renal denervation, all of the responses to activation of the baroreflex were similar to those observed before renal denervation. These findings demonstrate that the presence of the renal nerves is not an obligate requirement for achieving long-term reductions in arterial pressure during prolonged activation of the baroreflex.

Role of limbic peptidergic circuits in regulation of arterial pressure, relevant to development of essential hypertension

It is generally accepted that the essential hypertension (EH) is caused by interactions among congenital gene, multiple pathogenetic pressor factors, and disorder of physiologic depressor factors. The central nervous system may play a key role in the development of EH. The underlying mechanisms, however, are not well understood. Studies show that peptidergic transmitters in the limbic forebrain are involved in long-term regulation of arterial pressure and in the pathogenesis of EH. In the limbic forebrain there are peptidergic pressor and depressor circuits. The former includes corticotropin releasing factor-, substance P-, and angiotensin II-circuits; and the latter includes beta-endorphin- and atrial natriuretic peptide-circuits. These circuits extensively interconnect and interact with each other. The altered functions of them may be the pathogenesis of EH. In this review, we focus on the roles of limbic peptidergic circuits in regulation of arterial pressure, relevant to the neurogenetic mechanisms in developing EH.

Effects of High NaCl Diet on Arterial Pressure in Sprague-Dawley Rats with Hepatic and Sinoaortic Denervation

The Na(+) receptor that exists in the hepatoportal region plays an important role in postprandial natriuresis and the regulation of Na(+) balance during NaCl load. Thus it would be considered that a dysfunction of the hepatic Na(+) receptor might result in the elevation of arterial pressure under a condition of high NaCl diet. To elucidate this hypothesis, arterial pressure was continuously measured during three weeks of high NaCl diet (8% NaCl) in four groups of rats: (i) intact rats, (ii) rats with hepatic denervation (HD), (iii) rats with sinoaortic denervation (SAD), and (iv) rats with SAD+HD. During a 1-week normal NaCl diet period, there was no difference in arterial pressure among the four groups. A high NaCl diet had no influence on arterial pressure in intact or HD rats; however, it significantly increased by 11 +/- 3 mmHg in SAD rats. The addition of HD to SAD had no synergistic effect on arterial pressure; i.e., in SAD+HD rats, mean arterial pressure increased by 13 +/- 1 mmHg. In conclusion, sinoaortic baroreceptor, but not hepatic Na(+) receptor, has a significant role in the long-term regulation of arterial pressure on a high NaCl diet.

The sympathetic nervous system and hypertension: recent developments.

A major hypothesisfor the development of hypertension is that abnormal renal excretory function is critical for the initiation, development, and maintenance of primary hypertension.1 The renal body fluid feedback mechanism couples the long-term regulation of arterial pressure to extracellular volume (sodium and water) homeostasis via pressure natriuresis, whereby the kidneys respond to changes in arterial pressure by altering urinary sodium and water excretion. The obligatory requirement for maintenance of sodium and water balance by the kidneys is believed to be primary in the long-term control of arterial pressure. An increase in arterial pressure (via increases in total peripheral resistance or cardiac output or both) leads to an increased urinary sodium and water excretion via the pressure natriuresis mechanism, with consequent reduction in blood volume until arterial pressure is returned to normal. Thus, factors that decrease renal excretory function and disrupt the maintenance of sodium and water balance by the kidneys lead to an increase in arterial pressure, which is required to reestablish and maintain sodium and water balance. Based on computer modeling studies, a long-term increase in arterial pressure can only occur if there is a chronic and sustained decrease in renal excretory function. Increased renal sympathetic nerve activity (RSNA) is known to be a factor capable of decreasing renal excretory function.2,3 The renal effects of increased RSNA include increased renal tubular sodium reabsorption leading to renal sodium retention; decreased renal blood flow and glomerular filtration rate with renal vasoconstriction and increased renal vascular resistance; and increased renin release leading to angiotensin II production. Each of these renal functional alterations can decrease renal excretory function. The role of increased RSNA as being a critically important factor contributing to this renal excretory dysfunction in hypertension is strengthened by the fact that increased RSNA has been identified in hypertensive human …

Altered Natriuretic Peptide System in the Kidney in Hypertension

Diverse control systems are involved in the regulation of blood pressure, including renal, vascular, cardiogenic, neurogenic, and endocrine mechanisms. Among them, the kidney plays the dominant role in the long-term regulation of arterial pressure, in which the volume of extracellular fluid is regulated primarily by excreting or retaining sodium. Therefore, hypertension is usually associated with an altered renal sodium handling. There are mediators between increased renal perfusion pressure and decreased tubular reabsorption of sodium in the kidney. Although a dysfunction of nitric oxide system in the kidney appears to play a major role in the development of salt-sensitive hypertension, the regulation of atrial natriuretic peptide (ANP) may also be altered in hypertension. This review will discuss the altered regulation of ANP system in the kidney in different models of hypertension.

Oxidative stress in Dahl salt-sensitive hypertension.

The role of oxidative stress in the long-term regulation of arterial pressure, renal hemodynamics, and renal damage was studied in Dahl salt-sensitive rats. Twenty-eight Dahl S/Rapp strain rats, equipped with indwelling arterial and venous catheters, were subjected to a 3-week intravenous infusion of either low Na (0.9 mmol/d) or high Na (20.6 mmol/d) or the superoxide dismutase mimetic, 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol), at 125 micromol x kg(-1) x h(-1) plus low Na or high Na. After 21 days, mean arterial pressure was 140+/-3 mm Hg in the high-Na group, 118+/-1 mm Hg (P<0.05) in the high-Na/Tempol group, and unchanged in the low-Na/Tempol and low-Na groups. Tempol did not change renal blood flow, glomerular filtration rate, or glomerular cross-sectional area in rats subjected to the high-Na intake but did decrease urinary protein excretion, the percentage of sclerotic glomeruli, and the kidney weight to body weight ratio. In 15 additional Dahl S rats subjected to high or low Na intake for 3 weeks, renal cortical and medullary O2*- release increased significantly in the high-Na group when compared with the low-Na group. Tempol decreased both renal cortical and medullary O2*- release in the high- and low-Na rats, but the decrease in O2*- release was greater in high-Na rats. The data suggest that oxidative stress contributes to Dahl salt-sensitive hypertension and the accompanying renal damage.

Pathophysiology of essential hypertension: Role of the pump, the vessel, and the kidney

Essential hypertension is characterized by significant and persistent elevations in arterial pressure. Hypertension is a multifactorial disorder that may involve abnormalities in the functions of the heart pump, the blood vessels, and the kidneys. Short-term and long-term regulation of arterial pressure is influenced by changes in cardiac function, the peripheral vascular resistance, and the renal control mechanisms of plasma electrolytes and volume. Increases in the heart rate and stroke volume lead to increases in the cardiac output and could contribute to increases in arterial pressure particularly in relatively young individuals. Vascular endothelial cell dysfunction could lead to reduction in endothelium-derived relaxing factors such as nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor, or increased production of contracting factors such as endothelin-1 and thromboxane A2. Also, increased activity of signaling pathways of vascular smooth muscle contraction such as [Ca(2+)]i, protein kinase C, mitogen-activated protein kinase, and Rho kinase could enhance vasoconstriction. The decreased vascular relaxation and excessive vasoconstriction lead to significant increases in the peripheral vascular resistance and arterial pressure over time, particularly with aging. Alterations in body fluid regulation by the kidneys could lead to salt and water retention, increased plasma volume, and cardiac output. Also, activation of the renin-angiotensin system increases the levels of angiotensin II in the plasma, leading to generalized vasoconstriction, or locally in the kidneys, leading to salt and water retention. Individual changes in cardiac, vascular, or renal function seldom occur separately, and, if so, they may lead to mild or moderate increases in arterial pressure. Combined alterations in cardiac, vascular, and renal functions are more common and are often associated with pathologic increases in arterial pressure and established hypertension.

Differential control of intrarenal blood flow during reflex increases in sympathetic nerve activity.

The role of renal sympathetic nerve activity (RSNA) in the physiological regulation of medullary blood flow (MBF) remains ill defined, yet regulation of MBF may be crucial to long-term arterial pressure regulation. To investigate the effects of reflex increases in RSNA on intrarenal blood flow distribution, we exposed pentobarbital sodium-anesthetized, artificially ventilated rabbits (n = 7) to progressive hypoxia while recording RSNA, cortical blood flow (CBF), and MBF using laser-Doppler flowmetry. Another group of animals with denervated kidneys (n = 6) underwent the same protocol. Progressive hypoxia (from room air to 16, 14, 12, and 10% inspired O(2)) significantly reduced arterial oxygen partial pressure (from 99 +/- 3 to 65 +/- 2, 51 +/- 2, 41 +/- 1, and 39 +/- 2 mmHg, respectively) and significantly increased RSNA (by 8 +/- 3, 44 +/- 25, 62 +/- 21, and 76 +/- 37%, respectively, compared with room air) without affecting mean arterial pressure. There were significant reductions in CBF (by 2 +/- 1, 5 +/- 2, 11 +/- 3, and 14 +/- 2%, respectively) in intact but not denervated rabbits. MBF was unaffected by hypoxia in either group. Thus moderate reflex increases in RSNA cause renal cortical vasoconstriction, but not at vascular sites regulating MBF.

Endothelin and ET(A) receptors in long-term arterial pressure homeostasis in conscious nonhuman primates.

This study was designed to quantify the long-term contribution of endogenous endothelin-1 (ET-1) and ET(A) receptors to the regulation of arterial pressure under normal conditions in nonhuman primates. Therefore, mean arterial pressure (MAP) and heart rate were measured 24 h/day with the use of telemetry techniques in conscious cynomolgus monkeys under control conditions, during administration of an ET(A) selective receptor antagonist (ABT-627; 5 mg/kg, 2 times a day by mouth, 4 days), and a 6-day posttreatment period. Systemic ET(A) blockade reduced MAP (24 h) from 89 +/- 3 to 82 +/- 2 and 79 +/- 2 mmHg on days 1 and 4, respectively. Subsequently, MAP remained suppressed for 3 days posttreatment. Heart rate increased from 111 +/- 5 to 122 +/- 4 and 128 +/- 6 beats/min on days 1 and 4 of ABT-627, respectively, and remained above control for 3 days posttreatment. Plasma ET-1 concentration increased from 1.0 +/- 0.3 to 1.9 +/- 0.4 pg/ml in response to ABT-627 (day 4) but decreased to control values 4 days posttreatment. These data demonstrate a physiologically important role for endogenous ET-1 and ET(A) receptors in the long-term regulation of arterial pressure and plasma ET-1 levels in the conscious nonhuman primate.

Diversity of responses of renal cortical and medullary blood flow to vasoconstrictors in conscious rabbits.

The medullary microcirculation receives only about 10% of total renal blood flow, but plays a critical role in long-term arterial pressure regulation, so we need to better understand its regulation. Although there is evidence that circulating and locally acting hormones can differentially affect cortical and medullary blood flow in anaesthetized animals, there is little information from studies in conscious animals. This study is aimed (i) to develop a method for chronic measurement of cortical and medullary blood flow in conscious rabbits, and (ii) to test whether renal cortical and medullary blood flow can be differentially affected by intravenous (i.v.) infusions of various vasoconstrictor hormones in conscious rabbits. At preliminary operations, rabbits were equipped with single-fibre laser-Doppler flowprobes in the (left) renal cortex and medulla, and Transonic flowprobes for measuring cardiac output and renal blood flow. Intravenous angiotensin II (300 ng kg(-1) min(-1)), [Phe2,Ile3,Orn8]-vasopressin (30 ng kg(-1) min(-1)), noradrenaline (300 ng kg(-1) min(-1)), endothelin-1 (20 ng kg(-1) min(-1)) and N G-nitro-L-arginine (10 mg kg(-1)) increased mean arterial pressure (by 10-45% of baseline) and reduced heart rate (by 16-35%) and cardiac output (by 16-45%). Consistent with previous observations in anaesthetized rabbits, all treatments except [Phe2,Ile3, Orn8]-vasopressin reduced renal blood flow (13-63%) and cortical blood flow (16-47%), but medullary blood flow was significantly reduced only by [Phe2,Ile3,Orn8]-vasopressin (41%) and N G-nitro-L-arginine (42%). The diversity of these responses of cortical and medullary blood flow to i.v. infusions of vasoconstrictors provides further evidence for physiological roles of circulating and local hormones in the differential regulation of regional kidney blood flow.