Hypotensive mechanisms of antihypertensives based on the water tank model

Mechanisms of hypotensive action of antihypertensive drugs were theoretically considered using the water tank model on body fluid volume-blood pressure regulation. If a cock is attached to a tank with a base area corresponding to the reciprocal of total peripheral resistance (TPR) and water is poured into this tank at a rate corresponding to the amount of Na+ intake, then equilibrium should be achieved at a certain water level, volume, and output from the cock, which represent mean arterial pressure (MAP), cardiac output (CO), and urinary Na+ excretion rate. The height of the cock from the tank bottom and the size of the cock correspond to the x-intercept and slope of the renal function curve (pressure-natriuresis relationship). Vasodilators lowered the cock height and enlarged the base area (reduced TPR), resulting in an increase in the volume (CO). beta-Blockers not only lowered the height, but also decreased the size of the cock. Because they do not alter TPR (base area), CO (volume) must be reduced. Converting-enzyme inhibitors had the same effects on the height and size of the cock as beta-blockers, but enlarged the base area (reduced TPR), resulting in an increase in the volume (CO). Diuretics increased the cock size without affecting the cock height or the base area, resulting in a decrease in CO. The effects of antihypertensive drugs on the cock (kidney) seemed essential in their hypotensive action, similarly as abnormality of the renal function curve is essential in the genesis of hypertension. These analyses can illustrate schematically the hemodynamic changes induced by antihypertensive drugs.     

Renal function curve in patients with secondary forms of hypertension

The causative mechanisms of hypertension were investigated by studying the renal function (pressure-natriuresis) curve in patients with primary aldosteronism (n = 6) and renovascular hypertension (n = 6). Before and after radical operation (removal of adenoma in primary aldosteronism and percutaneous transluminal angioplasty in renovascular hypertension), dietary NaCl intake was altered from 10 to 13 g/day in Week 1 to 1 to 3 g/day in Week 2. Mean arterial pressure (MAP) and urinary sodium excretion were measured on the last 3 days of each week. By restricting sodium intake before operation, MAP was reduced from 122 +/- 7 to 113 +/- 7 mm Hg (p less than 0.025) in primary aldosteronism but not in renovascular hypertension (130 +/- 6 to 128 +/- 5 mm Hg). The renal function curve was drawn by plotting urinary sodium excretion on the ordinate and MAP on the abscissa before and after operation. The slope of the curve was analyzed between the plotted points, and each curve was extrapolated to zero sodium excretion as an estimate of the degree of shift of the curve along the MAP axis. Before, as compared with after operation, the extrapolated x-intercept of the curve was shifted rightward in both primary aldosteronism (111 +/- 7 vs 87 +/- 4 mm Hg; p less than 0.025) and renovascular hypertension (128 +/- 5 vs 95 +/- 2 mm Hg; p less than 0.025) and the slope was depressed in primary aldosteronism (16 +/- 1 vs 40 +/- 17 [mEq/day]/mm Hg; p less than 0.025) but not in renovascular hypertension (130 +/- 75 vs 40 +/- 13 [mEq/day]/mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hypertension in a nonhuman primate: humoral and hemodynamic mechanisms

The present study assessed the contribution of the renin-angiotensin system (RAS), dietary sodium, and cardiac output (CO) to the genesis of primate hypertensin in a one-kidney model which was developed to test species-specific renin inhibitors. Reduction of renal perfusion pressure increased mean arterial pressure (MAP) from 105 +/- 4 to 127 +/- 3 mm Hg (p less than 0.0005), associated with increased plasma renin activity (PRA) from 4.9 +/- 0.7 to 13.8 +/- 1.1 ng. ml-1.hr-1 (p less than 0.0005). Correlation of MAP with PRA yielded an r value of 0.662 (p less than 0.0005). Significant blood pressure elevation was obtained with both regular (R) and low sodium (LS) diet (p less than 0.0005), although the MAP change was greater with LS. With both R and LS diet, hypertension was associated with increased PRA (p less than 0.0005), and normotensive pressures were achieved with converting enzyme inhibitor (teprotide). The hemodynamic change with hypertension was an increase of systemic vascular resistance (SVR) from 0.89 +/- 0.12 to 1.17 +/- 0.09 units (p less than 0.05); cardiac output (CO) and central blood volume did not change significantly. Thus, acute hypertension, mediated by the RAS, was developed in a one-kidney primate model. The hemodynamic correlate of hypertension was increased SVR; CO and volume redistribution were not initiating factors.     

Increased peripheral resistance during reduced uterine perfusion pressure hypertension in pregnant rabbits.

The role of an increase in total peripheral resistance (TPR) and the contribution of angiotensin II (ANG II) to the hypertension induced by reduced uterine perfusion pressure (RUPP) was explored in pregnant rabbits. On the 22nd day of gestation, a catheter and a microthermocouple were placed in the aorta to measure mean arterial pressure (MAP) and cardiac output (CO), respectively. Three days later, RUPP was induced by a clip on the aorta proximal to the ovarian and distal to the renal arteries. Mean arterial pressure distal to the clip (uterine perfusion pressure) was reduced to 56 +/- 8% (mean +/- SD) of the initial level. Twenty-four hours later, MAP rose from 65 +/- 3 to 84 +/- 11 mm Hg; CO index decreased from 207 +/- 18 to 169 +/- 27 ml/min/kg; and TPR index increased from 0.32 +/- 0.03 to 0.51 +/- 0.08 mm Hg kg/ml/min, respectively (n = 7, all p less than 0.01). Sham-operated pregnant rabbits (n = 7) and non-P rabbits (n = 5) with a comparable distal aortic pressure reduction experienced no change in MAP or CO. Infusion of a receptor antagonist of angiotensin II (Sar1,Ile8-Ang II, 1 microgram/kg/min for 20 min) decreased MAP in sham-operated pregnant rabbits from 64 +/- 6 to 54 +/- 6 mm Hg (p less than 0.01) but did not change MAP in RUPP hypertensive rabbits (86 +/- 9 mm Hg before and 87 +/- 8 at the end of infusion, n = 6). These data indicate that RUPP in pregnant rabbits leads to a high resistance form of hypertension in which the formation of Ang II is not increased.     

Is sodium restriction effective treatment of borderline and mild essential hypertension? A long-term haemodynamic study at rest and during exercise

Blood pressure (BP) may fall during moderate sodium restriction in patients with essential hypertension (EH). Few data are available on the haemodynamic changes associated with sodium restriction and exercise data are lacking. We studied the long-term haemodynamic effect of reduced sodium intake in 19 men aged 16-51 years with mild and borderline EH. Cardiac output (CO; by Cardiogreen) and intra-arterial BP were measured at rest and during exercise before and after 9 months therapy. Sodium excretion was reduced by 75 mmol/24 h (36%) from a mean of 209 mmol/24 h and the sodium:potassium (Na:K) ratio fell by 0.75 from 2.17. Intra-arterial pressures fell by 3-5% (P less than 0.05) at rest, both supine and sitting, and during 50, 100 and 150 W bicycle exercise. Body weight and body fluid volumes (isotope dilution) remained unchanged. Haemodynamically, the fall in BP was due to reduction in CO ranging from 7-12% at rest and during exercise, while total peripheral resistance (TPR) rose by 4-10%. Stroke volume and heart rate fell by 2-9%. We conclude that moderate sodium restriction was not an efficient treatment in our patients with borderline and mild EH. The slight reduction in BP was associated with a fall in CO but without reduction of TPR. Thus, the main haemodynamic disturbance of established EH, that is an increase in TPR, was not normalized by 9 months sodium restriction.     

Urinary Sodium Excretion and Ambulatory Blood Pressure Findings in Patients With Hypertension

Use of ambulatory blood pressure (BP) monitoring (ABPM) allows for identification of dipping, nondipping, extreme dipping, and reverse dipping of BP. Using office BP and ABPM, hypertension subtypes can be identified: sustained normotension (SNT), white‐coat hypertension, masked hypertension, and sustained hypertension. The comparison of hemodynamic parameters and salt intake has not been investigated among these patient groups. Office BP, ABPM, augmentation index (AIx), pulse wave velocity (PWV), cardiac output (CO), and total peripheral resistance (TPR) were automatically measured. Estimation of salt intake was assessed by 24‐hour urinary sodium excretion. Urinary sodium excretion was not different among groups. AIx, PWV, CO, and TPR were lowest in patients with SNT. CO was lowest while AIx adjusted for a heart rate of 75 beats per minute, PWV, and TPR were highest in the extreme dipper group. No relationship was detected between hypertension subtypes and urinary sodium excretion.     

Renal denervation decreases blood pressure in DOCA-treated miniature swine with established hypertension

The role of renal sympathetic nerve activity (RSNA) in the maintenance phase of essential hypertension has not yet been clearly defined. Renal function and mean arterial pressure (MAP) were studied in four Yucatan miniature swine (YMS) with established DOCA hypertension prior to and for 3 weeks after surgical renal denervation (RDX). During the first week post-RDX, MAP decreased from 141 /+- 6 to 121 +/- 3 mm Hg (P less than .05), while sodium balance increased from 0.32 +/- 0.05 to 0.95 +/- 0.14 mEq/kg/day (P less than .05). By 3 weeks post-RDX, MAP remained below normotensive levels while sodium balance returned to the pre-RDX value. There was no significant change in potassium or water balance after RDX. Thus, in DOCA-YMS the renal nerves are important in the maintenance of hypertension. The reduction in MAP with RDX in the absence of a natriuresis suggests a role for renal afferent nerve activity.     

Structural factors increase blood pressure through the interaction of resistance vessel geometry with neurohumoral and local factors: estimates in rabbits with renal cellophane-wrap hypertension with intact effectors and during neurohumoral blockade

BACKGROUND : The structural changes in hypertension include narrowing of the lumen of the large resistance vessels and an increase in their wall thickness : lumen ratio. Their haemodynamic role has been controversial. OBJECTIVE : To examine resting haemodynamics and the responses to graded drug-induced changes in tone in renal cellophane-wrap (wrap) and sham-operated (sham) rabbits, when their neurohumoral effectors were intact and during high-level blockade. METHODS : Each rabbit was implanted with a flow probe for measuring cardiac output, had catheters inserted for drug infusions, and underwent mean arterial pressure (MAP) measurements. Resting values were determined and we infused graded doses of dilator and constrictor drugs: acetylcholine or adenosine; angiotensin II or methoxamine. The dilator and constrictor dose-response curves were combined into a single relationship for MAP, cardiac output, total peripheral conductance (TPC) and heart rate; total peripheral resistance (TPR) was estimated as 1/TPC. RESULTS : Throughout the range of vascular tone and with intact effector function, MAP was greater and TPC lower in wrap than in sham rabbits, and cardiac output was the same in both groups. The ratios of wrap : sham slopes of the log dose-response regression lines were 0.47 for TPC, 2.04 for TPR and 1.89 for MAP. Thus MAP and TPR responses were enhanced to the same degree in wrap rabbits. During neurohumoral block, baroreflex-mediated heart rate responses were abolished. In addition, resting vascular tone was lower than with intact effectors in both wrap and sham rabbits; however, the ratios of wrap : sham slopes for TPC and TPR were similar to those with intact effectors, whereas the ratio for the slope for MAP was slightly smaller, although still enhanced. CONCLUSION : In wrap hypertension, the enhanced MAP and TPR responses are in accord with an interaction between vascular geometry and the sum of altered neurohumoral + local activity, plus a rarefaction component.     

The second Sir George Pickering memorial lecture. What regulates whole body autoregulation? Clinical observations

The autoregulation theory of essential hypertension states that the characteristic haemodynamic derangement of this disease, i.e. increased vascular resistance, is a homeostatic response to abnormal sodium retention by the kidneys. The postulated relationship between arterial pressure and urinary sodium excretion is disturbed in such a way that a higher than normal pressure is required for sodium excretion to keep up with intake. This will initially expand plasma volume and raise cardiac output. However, hyperperfusion of the tissues will ultimately induce vasoconstriction, presumably by greater than normal wash-out of vasodilator metabolic products. Thus, cardiac output will be restored. Some elements of this theory are not supported by current evidence, but the key element, i.e. the assumption that increased vascular resistance is somehow dependent on abnormal renal sodium handling, is consistent with the following clinical observations: Arterial pressure and urinary sodium excretion are directly correlated over a wide range of pressures in patients with autonomic failure, both acutely during titling and chronically with changes in posture during a 24-h period. The failure to demonstrate pressure-natriuresis in normal subjects may therefore be related to the amplifying effect of the sympathetic nervous system on this mechanism, so that small changes in pressure are capable of inducing large changes in sodium excretion. The pressure-natriuresis curve in patients with autonomic failure is shifted to higher pressures by administration of aldosterone, which is consistent with an important role of renal sodium retention in mineralocorticoid hypertension. Measurements of total extracellular fluid volume, plasma volume/interstitial fluid volume ratio, transcapillary escape rate of serum albumin, cardiac output and arterial pressure at timed intervals during the development of hypertension, in patients exposed to mineralocorticoid excess, or during the reversal of hypertension in nephrectomized patients treated with ultrafiltration haemodialysis, revealed an association of increased total peripheral resistance with a reduced plasma volume/interstitial fluid volume ratio and an increased transcapillary escape rate of serum albumin. This association has also been observed in cross-sectional studies of patients with essential hypertension and suggests that part of the increase in resistance is located at a post-capillary level. It may be related to compression of collapsible venules and veins due to abnormally increased interstitial fluid pressure, not only in sodium-dependent secondary forms of hypertension but also in essential hypertension.(ABSTRACT TRUNCATED AT 400 WORDS)     

Terminal aortic response to sodium intake is the major determinant of total peripheral resistance in elderly hypertensives.

Thirty-four elderly patients were studied using a Doppler flowmeter during different sodium intakes. Salt increased mean blood pressure and cardiac output (CO), while total peripheral resistance (TPR) remained unchanged. Neither carotid nor terminal aortic resistance changed, while coeliac, superior mesenteric or renal resistance increased. There was a significant and direct correlation (r = 0.82) between the change in TPR and that in terminal aortic resistance. Salt-sensitive patients were divided into two subgroups; the SST group in which sodium loading increased TPR more than CO, and the SSC group in which salt loading increased CO more than TPR. Terminal aortic resistance increased in the SST, decreased in the SSC, and remained unchanged in the non-salt-sensitive group with salt loading. The terminal aortic vascular bed received much of the increase of CO in the SSC patients. In the SST group, the contribution of the individual vascular area to increased TPR was assessed, which revealed that terminal aortic response to sodium loading was the major determinant of increased TPR. We concluded that the responses of terminal aortic vascular bed to sodium loading contributed to the changes in TPR.     

Effect of intravertebral angiotensin II on cardiac output and its distribution in conscious dogs

Intravertebral infusion of angiotensin II (Ang II) increases mean arterial pressure (MAP), but the contribution of cardiac output (CO) and total peripheral resistance (TPR) to this increase is unclear. In the present study, the effects of Ang II infusion on CO and regional blood flow was determined by the microsphere technique in eight conscious, chronically catheterized dogs. Ang II was infused into both vertebral arteries at 0.33 and 1.0 ng/kg/min, and intravenously at 0.66, 2.0 and 5.0 ng/kg/min. Intravertebral infusion of Ang II at 0.33 ng/kg/min increased MAP by increasing CO without changing TPR or peripheral plasma Ang II concentration. MAP also was increased with intravertebral infusion of Ang II at 1.0 ng/kg/min, but this resulted from small increases in both CO and TPR. In contrast, intravenous infusion of Ang II at 2.0 and 5.0 ng/kg/min increased MAP by increasing TPR in association with a decrease in CO. The increase in CO with intravertebral infusion of Ang II at 0.33 ng/kg/min was distributed primarily to the muscles, kidneys, heart, and brain. Intravenous infusion of Ang II at 5.0 ng/kg/min and, to a lesser extent, 2.0 ng/kg/min decreased blood flow to the skin, splanchnic region, and kidneys. These data indicate that the increase in MAP produced by a low intravertebral dose of Ang II results from an increase in CO, which is distributed primarily to the muscle, kidney, heart, and brain. In contrast, the increase in MAP produced by a higher intravertebral dose of Ang II results from increases in CO and TPR. This latter action is apparently due to a peripheral action of Ang II to increase resistance in the skin, splanchnic, and renal circulations.     

Effects of high salt intake on hemodynamic responses to isometric exercise in normotensive subjects and in patients with essential hypertension

Hemodynamic responses to isometric exercise were compared between 9 normotensive subjects (NT) and 16 patients with essential hypertension (EH) before and during high salt intake. The subjects were hospitalized and placed on a diet containing 6g of salt per day. Baseline hemodynamic studies were carried out on supine subjects before and 3 min after isometric exercise (30% of the maximal voluntary handgrip). Plasma concentration of norepinephrine (PNE) was also measured. Brachial arterial pressure was directly recorded and cardiac output (CO) was measured by the dye-dilution technique using a cuvette. The hemodynamic studies were repeated on the 5th day of a high salt diet (16g of salt per day). Retention of sodium was calculated on a daily basis by measuring the actual intake of sodium and 24-hour urinary excretion of sodium. Pressor responses to isometric exercise were significantly greater in the EH than in the NT group. Patterns of hemodynamic responses were different in the 2 groups, i.e., the elevation of arterial pressure was maintained by an increase in CO in the NTs, while it was maintained by increases in CO and total peripheral vascular resistance (TPR) in the EHs. The increase in CO was significantly greater in the NT than in the EH group [15 +/- 3 (mean +/- SE) vs 7 +/- 1%, p less than 0.05]. Although the salt loading reduced heart rate similarly in both groups (-9.0 +/- 2.1, p less than 0.01, in the NTs and -11.9 +/- 2.9%, p less than 0.01, in the EHs), the high salt diet did not significantly alter mean arterial pressure (MAP), CO or TPR in either group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of salt, prostaglandin, and captopril on vascular responsiveness in essential hypertension

To examine the influence of dietary sodium, prostaglandin, and captopril on vascular reactivity, 12 patients with essential hypertension (EH) and seven normotensive subjects (NT) were given a high sodium diet and thereafter a low sodium diet, each for ten days. Indomethacin (IND) (150 mg/d) was administered during the last three days of each dietary period. Blood pressure and cardiac output (CO) (by impedance cardiography) were measured during the angiotensin II (Ang II) infusion before and after the IND treatment of each dietary period. In eight patients with EH, captopril 100 mg was given before Ang II infusion. EH patients were classified as either salt sensitive (SS) or nonsalt sensitive (NSS). The mean blood pressure (MBP) response to Ang II was significantly higher on high sodium intake than on low sodium intake in NSS and NT, but not in SS. IND significantly increased the MBP response to Ang II on low sodium intake in NSS and NT, but not in SS. IND significantly increased the TPR response to Ang II on low sodium intake, remarkably in NSS and NT compared with SS. Salt sensitivity (% decrease in MBP from high to low sodium intake) highly correlated with the increase in the TPR response to Ang II by IND on low sodium intake (r = -0.90). After captopril administration, IND still increased the MBP and TPR response to Ang II on low sodium intake. These results suggest that the modulation of the vascular responsiveness to Ang II by prostaglandins is altered by sodium balance and salt sensitivity in EH.     

Role of vasopressin in regulation of sodium excretion

It has been proposed that arginine vasopressin (AVP) contributes to the regulation of renal sodium excretion by direct intrarenal actions, by neural-hormonal interactions, and via secondary effects of fluid volume retention. The present studies were designed to determine the extent to which the natriuretic effects of AVP are secondary to volume expansion. Three groups of dogs were studied: the first was infused with AVP for 2 weeks in amounts that increased plasma levels from 3 to 15 pg/mL, while water intake was maintained constant by intravenous (iv) water infusion. The second group received the same amount of AVP and was permitted to drink ad libitum. The third group was infused with the same amount of AVP, while total body weight and volume were maintained at a constant level by use of an electronically servo-controlled water infusion system. The results showed a large increase in total body weight (+1.5 kg) and arterial pressure (mean arterial pressure (MAP); +40 mm Hg) in dogs receiving a fixed water intake. This was accompanied by a continuing natriuresis over a 2-week period and severe hyponatremia (115 mEq/L). Dogs allowed ad libitum drinking retained much less fluid (+0.5 kg). MAP was not significantly elevated, and natriuresis did not occur in this group, but hyponatremia was observed (130 mEq/L), and plasma renin activity (PRA) was suppressed. Servo-controlled dogs exhibited no change in MAP, plasma sodium, or PRA, and only a small (-15 mEq) natriuresis occurred on day 1 of AVP infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of the antihypertensive effect of a thiazide diuretic in angiotensin II-induced hypertension

OBJECTIVES : The antihypertensive effect of thiazide diuretics in angiotensin II induced hypertension has never been characterized. In the current study, we sought to determine the effect of a thiazide diuretic on arterial pressure and renal fluid excretion in rats receiving a chronic intravenous infusion of angiotensin II while on fixed normal or high sodium intakes. DESIGN AND METHODS : Male rats were chronically instrumented with arterial and venous catheters for drug injection and direct daily measurements of blood pressure and heart rate. Rats were maintained on high salt intake (HS), 6 mEq/day, or on normal salt intake (NS), 2 mEq/day. Rats were randomly assigned to four groups: HS and NS with 15 day angiotensin II infusion (5 ng/min) and HS and NS without angiotensin II infusion. Trichlormethiazide (TCM), a thiazide diuretic, was orally administered, approximately 10 mg/kg per day, for the middle 5 days of angiotensin II infusion. RESULTS : Only HS rats receiving angiotensin II infusion became hypertensive. Angiotensin II infusion did not produce changes in heart rate, sodium balance or water balance. Chronic administration of TCM significantly reduced mean arterial pressure (MAP) within 24 h in HS rats receiving angiotensin II, but did not affect MAP in any other group. TCM produced a similar loss of Na+ and water in all rats. Blood volumes and plasma electrolytes did not change during the study. CONCLUSIONS : The antihypertensive effects of thiazide diuretics are not due exclusively to volume depletion. We propose that salt and water loss caused by TCM may lower MAP by impairment of salt-sensitive pressor mechanisms activated by angiotensin II.     

Nisoldipine. Central haemodynamics at rest and during exercise in essential hypertension: acute and chronic studies

Calcium blockers may reduce contractility of vascular smooth muscle as well as that of myocardial cells. Therefore, falls in both total peripheral vascular resistance (TPR) and cardiac output (CO) might be responsible for a fall in blood pressure (BP) caused by calcium blockers in essential hypertension. We have studied the acute and chronic haemodynamic effects of nisoldipine (a new calcium blocker) in 19 patients with essential hypertension at rest in the supine and sitting positions and during 100-W dynamic exercise to investigate whether CO might be compromised by acute and chronic calcium blockade. Intra-arterial pressure, CO (by Cardiogreen), stroke volume, heart rate and TPR were measured hourly after the first dose of 10 mg nisoldipine (acute study) and then after 1 year of nisoldipine treatment (mean dose 25 mg; chronic study). The maximal first dose response was seen after 1 h, i.e. a fall in intra-arterial pressure (9%) and TPR (19%) and a reflex rise in heart rate (9%) and CO (12%). The effects levelled off during the next 2 h. After 1 year of treatment there was a more marked reduction in BP: at rest intra-arterial pressure fell (14% supine, 16% sitting) due to fall in TPR (19%) but without significant changes in heart rate or CO; during 100-W exercise, intra-arterial pressure fell (14%) due to reduction in both TPR (7%) and CO (6%). In conclusion, nisoldipine lowers BP by reducing TPR, both acutely and chronically. The initial reflex tachycardia and rise in CO disappear during long-term treatment, probably due to resetting of the baroreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute and long-term hemodynamic effects of tiapamil at rest and during exercise in essential hypertension

Summary The first dose and long-term hemodynamic responses to tiapamil—an aralkylamide calcium- channel blocker—were studied both at rest and during exercise in 18 male patients (mean age, 45 years) with essential hypertension (EH). Blood pressure (BP) was measured intra-arterially, cardiac output (CO) was measured by dye dilution and heart rate (JR) was measured by electrocardiogram. One hour after the first oral dose of 600 mg tiapamil, mean arterial pressure (MAP) fell 14%. Total peripheral resistance (TPR) fell 21%, while HR and CO increased 7% and 11%, respectively. There-after the effects leveled off. After 11 months of chronic tiapamil therapy (mean dose 980 mg per day), MAP was reduced 11% at rest sitting. The reduction in BP was associated with a modest reduction in TPR. Similar responses were seen at rest supine and during 100-W bicycle exercise. A small reduction was seen in HR while CO was preserved. In conclusion, tiapamil exerts a moderate antihypertensive effect, both at rest and during exercise, through reduction of TPR without a fall in heart pump function. The long-term hemodynamic changes are rather similar to those of verapamil.     

Effect of acute NaCl depletion on NaCl-sensitive hypertension in borderline hypertensive rats.

OBJECTIVES: The borderline hypertensive rat (BHR) is the first generation offspring of a mating between a female spontaneously hypertensive rat and a male normotensive Wistar-Kyoto rat. With increased dietary NaCl intake, the BHR develops hypertension and augmented cardiovascular and renal responses to acute environmental stress. This investigation sought to examine the role of extracellular fluid volume (ECFV) in these changes. DESIGN: Three groups of 16-week-old BHR were studied: (1) rats on a 1% NaCl diet for 12 weeks; (2) rats on an 8% NaCl diet for 12 weeks; and (3) rats on an 8% NaCl diet for 12 weeks plus furosemide (50 mg/kg, i.p., twice daily) for the preceding 2 days. METHODS: Rats were chronically instrumented for the measurement of mean arterial pressure (MAP), heart rate and renal hemodynamic, excretory and sympathetic nerve activity responses to acute environmental stress (acute air jet stress). ECFV was measured as inulin space. RESULTS: BHR fed an 8% NaCl diet had increased MAP, urinary sodium excretion and ECFV compared with those fed a 1% NaCl diet; they also exhibited augmented pressor, tachycardic, renal sympathetic nerve excitatory and antinatriuretic responses to acute environmental stress. When 8% NaCl-diet BHR were treated with furosemide for 2 days, arterial pressure, urinary sodium excretion, ECFV and cardiovascular and renal responses to acute environmental stress returned to values seen in 1% NaCl-diet BHR. CONCLUSIONS: The hypertension and increased cardiovascular and renal responses to acute environmental stress produced by increased dietary NaCl intake in BHR derive from a central nervous system site of action via a mechanism(s) related to ECFV and/or sodium.     

Forebrain contributions to one-kidney renal hypertension in the rabbit

Electrolytic lesions were placed along the anteroventral wall of the third cerebral ventricle (AV3V region) in 10 albino rabbits (AV3V-X), and sham lesions were produced in 10 additional rabbits (SHAM). Two to 3 weeks later, all rabbits underwent unilateral nephrectomy and renal artery stenosis (clip I.D. = 0.508 mm). During a 1-week control period, and for 4 weeks after renal artery stenosis, measurements were made of mean arterial pressure (MAP), heart rate, body fluid compartment volumes, plasma electrolytes, and daily sodium, potassium, and water balances. Four weeks after renal artery stenosis (RAS), cardiovascular responses to norepinephrine (NE), angiotensin II (AII), saralasin, and autonomic blockade were obtained in the conscious animals. In SHAM rabbits, MAP rose from 77 to 117 mm Hg 4 weeks after RAS. In AV3V-X rabbits, MAP rose from 77 to only 92 mm Hg 4 weeks after RAS. Body fluid compartment volumes, plasma electrolytes, and fluid, sodium, and potassium balances showed similar modest changes in both groups of rabbits. Neither saralasin infusion nor autonomic blockade caused significantly different changes in MAP between SHAM and AV3V-X rabbits 4 weeks after RAS. However, pressor responses to both NE and AII were significantly less in AV3V-X rabbits at this time. It is concluded that one-kidney, one clip renal hypertension involves activation of neurohormonal pressor mechanisms originating in the forebrain, and that the expression of these pressor mechanisms in part includes an increase in cardiovascular reactivity.     

Effects of calcium antagonists on deranged modulation of the renal function curve in salt-sensitive patients with essential hypertension

Two subsets of patients with essential hypertension have been identified based on their sensitivity to dietary sodium intake: the salt-sensitive and the salt-resistant patients. The renal function curve in salt-resistant patients is shifted to higher blood pressure levels but it remains parallel to that of normal subjects. On the contrary, the slope of the renal function curve in salt-sensitive patients is considerably depressed. It is postulated that this derangement may be related to an abnormal relation between sodium intake and sympathetic nervous system activity. It is also postulated that a link exists between abnormalities of sodium and calcium metabolism in hypertension and that reduced renin release, increased sympathetic activity and reduced renal sodium excretion in salt-sensitive patients may be related to a defect in sodium-linked cellular calcium transport. Calcium antagonists revert the derangements in the renal function curve and in renin release in salt-sensitive patients.