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Angiotensin II causes vasoconstriction via the type 1 receptor (AT(1)R) and vasodilatation through the type 2 receptor (AT(2)R). Both are expressed in muscle microvasculature, where substrate exchanges occur. Whether they modulate basal muscle microvascular perfusion and substrate metabolism is not known. We measured microvascular blood volume (MBV), a measure of microvascular surface area and perfusion, in rats during systemic infusion of angiotensin II at either 1 or 100 ng/kg per minute. Each caused a significant increase in muscle MBV. Likewise, administration of the AT(1)R blocker losartan increased muscle MBV by >3-fold (P<0.001). Hindleg glucose extraction and muscle interstitial oxygen saturation simultaneously increased by 2- to 3-fold. By contrast, infusing AT(2)R antagonist PD123319 significantly decreased muscle MBV by >or=80% (P<0.001). This was associated with a significant decrease in hindleg glucose extraction and muscle oxygen saturation. AT(2)R antagonism and inhibition of NO synthase each blocked the losartan-induced increase in muscle MBV and glucose uptake. In conclusion, angiotensin II acts on both AT(1)R and AT(2)R to regulate basal muscle microvascular perfusion. Basal AT(1)R tone restricts muscle MBV and glucose extraction, whereas basal AT(2)R activity increases muscle MBV and glucose uptake. Pharmacological manipulation of the balance of AT(1)R and AT(2)R activity affords the potential to improve glucose metabolism.

Endothelin (ET) exerts powerful pressor actions primarily through activation of the ET(A) receptor subtype. The ET(B) receptor (ET(B)R) subtype, on the other hand, is generally thought to initiate physiological actions that decrease arterial pressure. Such actions include clearing ET from the bloodstream, initiating endothelium-mediated vasodilation, and facilitating renal sodium and water excretion. The effect of long-term activation of the ET(B)R on arterial pressure, however, never has been directly tested. In this study we evaluated cardiovascular responses to chronic (5-day) activation of ET(B)R in male rats using continuous intravenous infusion of the selective agonist sarafotoxin 6c. Surprisingly, we found that sarafotoxin 6c caused a sustained increase in arterial pressure that rapidly reversed on termination of infusion. The hypertension was associated with increased renal excretion of sodium and water and decreased plasma volume. Alterations in daily sodium intake did not affect the magnitude of the hypertension. Hemodynamic studies revealed a decreased cardiac output and increased total peripheral resistance during sarafotoxin 6c infusion. Infusion of sarafotoxin 6c caused a small increase in plasma ET levels. Nevertheless, the hypertension was not affected by coadministration of a selective ET(A) receptor antagonist (atrasentan) but was completely prevented by treatment with a combined ET(A) receptor and ET(B)R antagonist (A186280). These experiments reveal for the first time that chronic activation of ET(B)R in rats causes sustained hypertension.

We assessed the clinical and pharmacological profile of the orally active V(1) vascular vasopressin (AVP) receptor nonpeptide antagonist SR49059 (SR) during the osmotic stimulation of AVP release in hypertensive patients. In a double-blind crossover-versus-placebo study, 24 untreated stage I or II essential hypertensive patients (12 whites and 12 blacks) received a single 300 mg oral dose of SR 2 hours before the stimulation of AVP secretion with a 5% hypertonic saline infusion. Hemodynamic, humoral, and hormonal parameters were monitored for up to 28 hours after drug administration. SR did not alter blood pressure or heart rate before the saline infusion and did not reduce the blood pressure increment induced by the hypertonic saline infusion. However, the blood pressure peak at the end of the hypertonic saline infusion was slightly lower in the presence of SR (P=0.04). Heart rate was significantly faster between 4 and 6 hours after SR administration (P=0.02). The rise in plasma sodium and osmolality triggered by the saline infusion was not modified by SR, but AVP release was slightly greater in the presence of SR (P<0.0003). AVP-induced aggregation of blood platelets in vitro was significantly reduced by SR, with a peak effect 2 hours after drug administration that coincided with the SR peak plasma concentration. Plasma renin activity and aldosterone before and after the saline infusion were not modified by SR. Urine volume and osmolality were not altered by SR administration. SR effects were similar in the 2 ethnic groups as well as in salt-sensitive versus salt-resistant patients. In a situation of AVP osmotic release and volume expansion in hypertensive patients, a single oral dose of the V(1) vascular AVP receptor nonpeptide antagonist SR49059, which is able to block AVP-induced platelet aggregation, exerts a transient vasodilation effect that is not associated with a sustained blood pressure reduction. SR49059 is a pure V(1) vascular receptor antagonist that is devoid of V(2) renal receptor actions.

We conducted longitudinal measurements of blood pressure and renal function in the conscious, chronically catheterized rat before and during acute nitric oxide synthase inhibition (N-nitro-L-arginine methylester [L-NAME], 37 micromol/kg IV) and then chronic administration of oral L-NAME (approximately 37 micromol/kg per 24 hours). These studies specifically investigate the impact on plasma and renal renin as well as volume status during the evolution of this hypertension in rats not subjected to acute experimental stress. Blood pressure progressively increased with chronic administration of L-NAME and reached values greatly above those seen with acute administration of L-NAME. There were parallel increases in renal vascular resistance and development of proteinuria, and glomerular filtration rate began to decline at day 21, coincident with the appearance of renal damage. Twenty-four-hour urinary nitrite and nitrate excretion remained depressed, reflecting reduced nitric oxide synthesis. The plasma renin activity was variable and only increased transiently at 21 days, thus the angiotensin II dependence of this hypertension is not caused by stimulated plasma renin activity. Despite severe hypertension, sodium intake and excretion were unchanged over the 21 days of L-NAME administration. Plasma volume was significantly reduced at days 2 and 12 of L-NAME administration; thus the prolonged plasma volume contraction must result from the acute natriuretic response to the initial acute L-NAME administration.

To determine if pregnancy alters the impaired renal vasodilator responses in hypertensive Dahl salt-sensitive (Dahl S) rats, we measured glomerular filtration rate and effective renal plasma flow and calculated renal vascular resistance before, during, and after renal vasodilation with glycine (0.17 mmol/kg per minute IV). Conscious, midterm (day 11 to 14) pregnant and age-matched virgin Dahl S and Dahl salt-resistant (Dahl R) rats were fed an 8% NaCl diet for 4 weeks (n = 6 per group). Mean arterial pressure was elevated (P < .05) in Dahl S compared with Dahl R rats, with no significant difference between pregnant and virgin animals in either group. Pregnancy resulted in significant increases in plasma volume, baseline glomerular filtration rate, and renal plasma flow and a significant decrease in renal vascular resistance. The glycine-induced increase in filtration rate in virgin Dahl S rats (27 +/- 4%) was less (P < or = .01) than pregnant Dahl S (60 +/- 4%) and either group of Dahl R (virgin, 43 +/- 3%; pregnant, 45 +/- 5%) rats. Similarly, the 21 +/- 4% increase in renal plasma flow in virgin Dahl S rats was less (P < or = .01) than the pregnant Dahl S (45 +/- 4%) and either pregnant (45 +/- 5%) or virgin (45 +/- 5%) Dahl R rats. Glycine decreased renal vascular resistance only 12 +/- 2% in the virgin Dahl S compared with 31 +/- 3% in the pregnant Dahl S rats and 30 +/- 4% and 28 +/- 3% in pregnant and virgin Dahl R rats.(ABSTRACT TRUNCATED AT 250 WORDS)

With increased dietary NaCl intake (8% NaCl), borderline hypertensive rats (BHR) develop hypertension and exhibit an exaggerated natriuresis in response to intravenous isotonic saline volume expansion. The exaggerated natriuresis is mediated by the concurrent exaggerated withdrawal of efferent renal sympathetic nerve activity since prior renal denervation eliminates the exaggerated natriuretic response. It was the objective of the present study to examine cardiac volume receptor reflex control of efferent renal sympathetic nerve activity in BHR made hypertensive by increased dietary NaCl intake. BHR were fed either 1% or 8% NaCl from age 4 to 16 weeks. BHR fed 8% NaCl were hypertensive (148 +/- 9 mmHg) compared with BHR fed 1% NaCl (115 +/- 6 mm Hg, p < 0.05). In one protocol, measurements of right atrial pressure and efferent renal sympathetic nerve activity were made in sinoaortic-denervated BHR before and during a 10% body weight intravenous isotonic saline volume load. Compared with 1% NaCl BHR, 8% NaCl BHR showed both a greater maximal inhibition of efferent renal sympathetic nerve activity (-67 +/- 4% versus -31 +/- 3% of control, p < 0.05) and gain (-22.0 +/- 2.3 versus -9.7 +/- 1.7%/mm Hg, p < 0.05). In a second protocol, measurements of efferent renal sympathetic nerve activity were made in sinoaortic-denervated BHR before and during graded frequency stimulation of the central portion of the sectioned vagus nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

In severe preeclampsia, short-term peripartum management of hypertension with hydralazine is complicated by relatively prolonged hypotensive episodes, resulting in fetal distress. We hypothesized that nitroprusside's rapid onset and brief antihypertensive action would permit more controlled blood pressure reduction. Nitroprusside was infused into 10 invasively monitored subjects until mean arterial pressure either 1) was gradually reduced 10-20% or 2) fell abruptly. Subjects fell into two groups, defined by whether the hypotensive effect of nitroprusside was accompanied by a fall in heart rate (group A, n = 8) or a rise (group B, n = 2). Group B showed the expected sinoaortic baroreceptor reflex elevations in heart rate (+17 +/- 6 beats/min) in response to moderate falls in mean arterial pressure (-32 +/- 9 mm Hg) elicited by moderate doses (1.03 +/- 0.23 micrograms/kg/min). However in group A, steep reductions in mean arterial pressure (-75 +/- 22 mm Hg, p less than 0.0001), significantly greater than in group B (p less than 0.05), occurred at much lower doses (0.35 +/- 0.23 micrograms/kg/min; p less than 0.05) and were accompanied by falls in heart rate (-21 +/- 7 beats/min). The apparently paradoxical falls in heart rate and extreme hypotensive responses in group A indicate severe circulatory compromise, corresponding to the cardiac and vasomotor depression that characterizes severe hemorrhage and other forms of acute/severe hypovolemic hypotension. This hemodynamic pattern represents a cardiopulmonary baroreceptor reflex presumably related to the Bezold-Jarisch reflex. The appearance of this pattern in the present study probably reflects the imposition of nitroprusside's prominent venous dilator action on the relatively reduced blood volume that generally characterizes severe preeclampsia.

Recent evidence indicates that the anion accompanying sodium plays an important role in determining the magnitude of the blood pressure increase in response to a high dietary intake of NaCl. The purpose of this review is to describe studies of blood pressure responses to selective dietary sodium loading (without chloride) and to selective dietary chloride loading (without sodium) in several experimental models of salt-sensitive hypertension and in hypertensive humans. The full expression of salt sensitivity depends on high dietary intakes of both sodium and chloride. This observation has implications for understanding mechanisms contributing to NaCl-induced hypertension.

The antihypertensive, hemodynamic, and humoral effects of the new converting-enzyme inhibitor enalapril (MK-421) were assessed by sequential studies during 3 months of uninterrupted treatment (20 mg twice daily) in 10 hypertensive patients. Six achieved good blood pressure (mean arterial pressure) control with enalapril alone (from 126 +/- 7.0 mm Hg pretreatment to 105 +/- 1.6 mm Hg at 3 months, p less than 0.05). The other four required the addition of diuretics (hydrochlorothiazide 25 mg orally twice daily) at different stages of follow-up, with resultant blood pressure control (128 +/- 9.6 mm Hg pretreatment to 113 +/- 1.9 mm Hg at 2 months after the addition of diuretics). Neither the acute nor long-term blood pressure response could be predicted from the pretreatment levels of plasma renin activity. The blood pressure reduction during enalapril therapy was characterized by a decrease in total peripheral resistance (53 +/- 2.5 U X M2 pretreatment to 38 +/- 3.0 U X M2 at 3 months, p less than 0.05) with no significant change in cardiac output or heart rate. This lack of reflex tachycardia could not be ascribed to baroceptor dysfunction since the response to head-up tilt (the increase in diastolic blood pressure, in heart rate, and in plasma catecholamines) was normal and not significantly different from pretreatment response. Average blood volume did not change (91% +/- 4.3% of normal in the pretreatment period to 93% +/- 2.9% after 3 months of therapy, p = NS) despite the significant lowering of arterial pressure with enalapril alone (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneously hypertensive male rats (SHR) or normotensive Kyoto-Wistar (WKY) male rats underwent either sham or nerve growth factor antiserum (NGFAS) treatment during the first week of life. The NGFAS treatment prevented the development of hypertension in SHR but did not prevent the development of left ventricular groups in vivo under general anesthesia. After the recording of resting parameters, homologous whole blood was transfused until the rise in cardiac output reached a plateau. At rest, LV systolic pressure of the NGFAS-treated SHR was significantly lower than that of the sham-treated SHR and not statistically different from that of the WKY rat. The LV end diastolic pressures did not differ among the four groups. Both SHR groups had significantly lower cardiac, stroke, and contractility indices than di the WKY groups. Following vascular expansion, LV filling pressure, stroke index, and stroke work index rose in all groups. The response in the SHR was greater than that in WKY groups. Interestingly, the systolic pressure of the NGFAS-treated SHR rose to the same level as in the sham-treated SHR. Heart rate and calculated systemic vascular resistance fell following transfusion. The SHR appears to exhibit an altered response to increased filling pressure and increased afterload. Our findings are consistent with the concept of an alteration in the compliance of the LV in the SHR.

Male spontaneously hypertensive rats (SHR), 13 weeks old, received oral administration of captopril (SQ14,225) daily at a dose of 10 mg/kg or 30 mg/kg; or water at 2 ml/kg, for 6 weeks. Captopril suppressed the development of hypertension slightly at the lower dose and completely at the higher dose. At 6 weeks of dosing, hemodynamic parameters were measured by the tracer microsphere method and blood volume by the dilution method using 51Cr erythrocytes. Cardiac output (CO) increased and mean blood pressure decreased in a dose-dependent manner; thus, total peripheral resistance decreased. Cerebral and renal blood flows increased in a dose-dependent manner while blood flow to other organs tended to increase or remained unchanged. There was no significant differences in the circulating blood volume among the three groups. In conclusion, long-term blockade of angiotensin converting enzyme (ACE) with captopril dilated blood vessels in the whole body, especially in the brain and kidney, and lowered blood pressure without causing plasma expansion or tachycardia.

Compared with Dahl salt-resistant (R) rats, Dahl salt-sensitive (S) rats on a low salt diet have impaired cardiopulmonary baroreflex control of sympathetic nerve activity. The purpose of this study was to examine the sensitivity of cardiopulmonary baroreflex function in both strains of Dahl rats when they are challenged with a high salt diet. We studied Dahl R and S rats after 6 weeks of low and high salt diets. To assess cardiopulmonary baroreflex function, we measured decreases in splanchnic sympathetic nerve activity produced by increases in left ventricular end-diastolic pressure during graded volume expansion (dextran 75) after bilateral sinoaortic denervation. A given amount of infused volume produced comparable increases in left ventricular end-diastolic pressure in Dahl R rats on low and high salt diets but significantly greater decreases in sympathetic nerve activity in the high salt group than in the low salt group. Thus, the high salt diet augmented the sympathoinhibitory response to volume expansion in the Dahl R rats. In contrast, among the Dahl S rats equivalent increases in left ventricular end-diastolic pressure during volume expansion produced smaller sympathoinhibitory responses in the high salt group than in the low salt group. The gain of the cardiopulmonary baroreflex, expressed as the percentage decrease in sympathetic nerve activity per mm Hg increase in left ventricular end-diastolic pressure, was significantly increased by a high salt diet in Dahl R rats but tended to be decreased by a high salt diet in Dahl S rats.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was performed with Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rats to detect differences in cardiovascular hemodynamics and renal responses that might be involved in initiating salt-induced hypertension in DS rats. The effects of 4 weeks of 8% NaCl diet were studied in conscious, male DR and DS rats in which vascular and urinary catheters had been previously implanted. Results were compared with those obtained from control groups of DR and DS rats on 4 weeks of 1% NaCl diet. DR rats on 8% salt diet did not develop hypertension, and cardiac output and blood volume were unchanged; glomerular filtration rate, urinary flow, sodium excretion, and plasma atrial natriuretic factor (ANF) increased. DS rats on 8% salt diet developed hypertension, and cardiac output and blood volume increased; glomerular filtration rate, urinary flow, and sodium excretion did not change, despite an increase in ANF. DS and DR rats on 1% NaCl diet were subjected to ANF infusion. After ANF infusion DR rats had a decreased blood volume and an increased glomerular filtration rate, urinary flow, and sodium excretion; DS rats showed no significant changes in blood volume, glomerular filtration rate, urinary flow, or sodium excretion. ANF caused vasodilation in all regions studied in DR rats; DS rats showed vasodilation in all regions except the kidney. After acute volume expansion, although both DR and DS rats responded by an increase in cardiac output, only DS rats developed prolonged hypertension. This finding suggests an inadequate vasodilatory mechanism in DS rats. In response to acute volume expansion, renal resistance decreased in DR rats but not in DS rats. It is concluded that the primary hemodynamic disturbance in DS rats with salt-induced hypertension is an increase in cardiac output caused by blood volume expansion in the absence of any vasodilation. Comparison of the responses of DS and DR rats to high salt diets, ANF infusion, and acute volume expansion indicates that the salt-induced hypertension in DS rats is initiated by a diminished renal response to ANF.

We studied the total vascular pressure-volume relationship and cardiac output (CO) in conscious rats receiving DOCA-salt or sham treatment. The mean circulatory filling pressure (MCFP) was measured by briefly inflation an indwelling balloon in the right atrium, and the MCFP-blood volume (BV) relationship over +/- 10% of BV was determined by rapid blood infusion or withdrawal. CO was measured in separate experiments using Fick's principle. Arterial pressure-volume relationship was also determined in additional experiments on anesthetized rats. Compared with sham rats, the mean arterial pressure was unchanged at 1 week, increased at 2 weeks, and increased further thereafter in the DOCA-salt rats. The BV was unchanged at 1 week, expanded at 2 weeks, unchanged at 5 weeks, and contracted at 8 weeks. There were no significant changes in MCFP, total vascular compliance (the inverse of the slope), nor unstressed volume (extrapolated volume axis intercept) at 2, 5, and 8 weeks. Total vascular capacity, assessed as BV at MCFP of 7.6 mm Hg, increased at 2 weeks, was unchanged at 5 weeks, and decreased at 8 weeks. Arterial compliance decreased at 5 and 8 weeks. CO remained unaltered at 1, 2, 5, and 8 weeks. These results suggest that the altered total vascular capacity may serve to maintain a normal CO against a rising afterload in the conscious DOCA-salt hypertensive rats, and that the decreased total vascular capacity may be a secondary hemodynamic feature with progression of hypertension.

We have previously shown that weight gain in the dog results in an increase in blood pressure. To study the pathogenesis of the rise in blood pressure associated with weight gain, we compared the serial changes in blood pressure, body weight, sodium balance, plasma volume, and three hormones known to affect sodium balance (norepinephrine, insulin, and aldosterone) in seven dogs fed a high fat diet for 6 weeks and seven dogs fed a control diet. The sodium content of both diets was equal. During a 2-week control period, no differences were noted between the two groups. Weight gain was associated with a progressive increase in blood pressure (mean pressure increased by 18.5 +/- 2.1 mm Hg in the high fat group) and plasma volume (plasma volume increased from 1,426 +/- 202 to 2,053 +/- 250 ml in the high fat group). Sodium retention occurred after 1 week of the high fat diet and persisted. Over the 6-week period, the dogs on the high fat diet increased their cumulative sodium balance by 2,024 +/- 462 meq versus an increase of only 289 +/- 97 meq for the dogs on the control diet. In the high fat diet group of dogs, there was a significant relation between change in cumulative sodium balance and the change in blood pressure and plasma volume. After 1 week of the high fat diet, norepinephrine was the only hormone that significantly increased from baseline. Over the next 5 weeks norepinephrine increased no further, whereas fasting insulin and aldosterone progressively increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Diuretic therapy, by producing a negative salt and water balance, eliminates the false tolerance to sympatholytic drugs that often occurs during long-term monotherapy. This tolerance results from salt and water retention produced by the drugs. Review of published results suggests a primacy for arterial pressure reduction in this fluid because suppressed renal sympathetic activity should facilitate salt and water excretion through lessened alpha-adrenergic influence on tubular reabsorption, and beta-adrenergic inhibition would diminish renin release thus promoting natriuresis. The return of hypertension that characterizes the false tolerances seems paradoxical because these drugs cause venodilation, which should provide ample storage of expanded blood volume without affecting cardiac output. However, animal studies have suggested that dilated veins have decreased compliance; if that is so, in humans it would mean that fluid retention would be accompanied by a redistribution of blood into the central circulation, with a rise in cardiac output.

Increased levels of a humoral inhibitor of active sodium transport have been associated with the response to acute and chronic hypervolemia and various forms of experimental as well as human essential hypertension. In this report, we describe the purification of inhibitors of Na+, K+-adenosine triphosphatase (ATPase) from the plasma of volume-expanded individuals. Of the two amphipathic materials obtained, only one of the factors when present in high concentrations showed the slow time-dependent component of inactivation similar to that of the cardiac glycosides. Inhibition was reduced in the presence of plasma proteins and was freely reversible. Both factors inhibited potassium-dependent p-nitrophenylphosphatase activity and specific [3H]ouabain binding in a manner similar to the cardiac glycosides. In contrast to ouabain and vanadate, however, high concentrations of potassium or norepinephrine, respectively, did not affect the magnitude or kinetic characteristics of inhibition. Structural analysis by mass spectroscopy showed a mass of 444 for factor 1, whereas factor 2 was conclusively identified as lysophosphatidylcholine-gamma-palmitoyl. These factors probably inhibit Na+, K+-ATPase by a nonspecific mechanism involving reversible perturbation of lipid-enzyme interactions required for normal catalytic activity. The significance of these factors as modulators of sodium transport may be limited to pathological states associated with abnormalities in plasma protein binding or lipid metabolism. They do not appear to be directly related to the humorally mediated disturbance of cellular sodium transport in hypertension.

The involvement of postsynaptic alpha 2-adrenergic receptors in the adrenergic constriction of the capacitance vessels was studied in anesthetized, spontaneously breathing dogs under ganglionic blockade (hexamethonium, 10 mg/kg + 10 mg/kg/hr; methylatropine, 0.5 mg/kg). Effective vascular compliance was measured as an indicator of venous tone (blood volume was varied by +/- 4 ml/kg in an 11-minute cycle of infusion, withdrawal, withdrawal, and reinfusion) and was calculated from the correlation between the observed changes in central venous pressure and the changes in blood volume. Sympathetic activity and central venous pressure were lower and effective vascular compliance was higher than values in untreated conscious dogs. The alpha 2-agonist UK 14,304 (5-bromo-6-[imidazolin-2-ylamino]-quinoxaline; 0.04 and 0.12 micrograms/kg/min; n = 6) dose-dependently lowered compliance and increased central venous pressure to levels found in conscious dogs, as did the alpha 1-agonist methoxamine (10 and 30 micrograms/kg; n = 6). Rauwolscine (alpha 2-antagonist), 0.3 mg/kg, significantly attenuated the effects of UK 14,304, but not those of methoxamine, while prazosin (alpha 1-antagonist), 0.12 mg/kg, attenuated the effects of methoxamine, but not those of UK 14,304 (n = 6 each). Under beta-blockade (nadolol, 2 mg/kg; n = 12) venous tone was increased to about physiological levels by norepinephrine, 0.15 micrograms/kg/min i.v., or by neuronal norepinephrine release induced by tyramine, 10 micrograms/kg/min i.v. These increases were significantly attenuated by prazosin as well as by rauwolscine and were abolished by a combination of both. These results indicate that postsynaptic alpha 2-adrenergic receptors (in addition to alpha 1-adrenergic receptors) are functional in the venous system in vivo and contribute substantially to adrenergic sympathetic and humoral regulation of venous tone.

In spontaneously hypertensive rats (SHR), the progression (or absence of regression) of cardiac hypertrophy despite adequate blood pressure (BP) control by arterial vasodilators has been attributed to increased cardiac sympathetic activity. We evaluated changes in indices of general and cardiac sympathetic tone in relation to changes in cardiac anatomy during treatment of normotensive rats and SHR with hydralazine, 120 mg/L, or minoxidil, 120 mg/L of drinking water. In SHR, both vasodilators reduced BP rapidly and consistently. Significant increases in heart rate and plasma norepinephrine were observed only in the initial 2 days of arterial vasodilator treatment. After 5 weeks of treatment, marked increases in left and right ventricular sympathetic activity (as assessed by norepinephrine turnover rates) were present, but no increase was seen in heart rate and plasma norepinephrine. Intravascular volume expansion was observed on Day 14 of minoxidil and Day 35 of hydralazine treatment. Prolonged treatment with minoxidil induced significant increases in left ventricular internal diameter, as well as in left and right ventricular weights, but not in the wall thickness of the left ventricle. Treatment with hydralazine did not affect left ventricular weight and caused a small increase in the weight of the right ventricle. In normotensive rats, both vasodilators initially decreased BP, but tolerance developed within 1 to 2 weeks of treatment. Plasma norepinephrine and heart rate showed increases only at Day 1 of either treatment, whereas cardiac sympathetic hyperactivity persisted at 2 and 5 weeks of treatment. Changes in cardiac anatomy were qualitatively similar to those observed in SHR. We conclude that, during treatment of normotensive rats and SHR with arterial vasodilators, cardiac sympathetic hyperactivity persists and may be involved in the cardiac effects of arterial vasodilators. However, other mechanisms, such as chronic cardiac volume overload, may also play an important role, particularly with minoxidil.

The role of alpha 2-adrenergic receptor stimulation in the regulation of systemic vascular capacity and venous return, a major determinant of cardiac output, is not well understood. With the influence of the central nervous system isolated from the systemic circulation, the direct peripheral vascular effects of two specific, chemically distinct alpha 2-adrenergic receptor agonists, UK 14,304 and B-HT 920, were investigated in 19 dogs on total cardiopulmonary bypass with constant arterial perfusion and central venous pressure. Five-minute intra-arterial infusions of UK 14,304 (200 micrograms/min) resulted in increased arterial resistance (mean arterial pressure increased 18 +/- 4 [SEM] mm Hg; p less than 0.01) and a decrease in systemic vascular capacity (81 +/- 20 ml; p less than 0.01). This decrease in systemic vascular capacity appears to result from vasoconstriction, since there was no decrease in transhepatic resistance to portal flow and no significant change in hepatic vein flow to suggest redistribution of arterial blood flow. Yohimbine abolished both the arterial and systemic capacity effects, whereas prazosin did not. Intra-arterial administration of B-HT 920 (200 theta grams/min) in five dogs produced similar changes in arterial resistance and systemic capacity. These findings provide direct evidence for beta 2-adrenergic control, not only of arterial resistance but also of systemic vascular capacity, which in the intact animal would increase venous return to the heart.

Maximal vasodilator capacity of resistance vessels has been shown to be reduced in normotensive young men with a family history of hypertension. The present study attempted to examine whether venous distensibility is decreased in normotensive men with hypertensive relatives. The venous pressure-volume relationship was determined in the forearm with a water-filled plethysmograph in 17 normotensive young men with hypertensive relatives (mean blood pressure, 85 +/- 2 [SE] mm Hg; age, 22 +/- 1 years) and 18 young men with no family history of hypertension (mean blood pressure, 81 +/- 2 mm Hg; age, 22 +/- 1 years). The venous pressure-volume curve in men with hypertensive relatives as compared to that in men with no family history of hypertension was shifted toward the pressure axis (p less than 0.001). This findings suggests that venous distensibility is decreased in normotensive young men with hypertensive relatives. Administration of phentolamine, 1 mg/min i.v. for 5 minutes, did not alter venous distensibility, and venous distensibility after phentolamine administration was less in men with hypertensive relatives than in men with no family history (p less than 0.001), which suggests that decreased venous distensibility found in normotensive young men with hypertensive relatives was unlikely to be related to alpha-adrenergic mechanisms. These results suggest that normotensive young men with a family history of hypertension have vascular abnormalities that involve veins as well as arteries.

In a search for factors contributing to the sustained blood pressure (BP) elevation in acutely volume-loaded animals, dextran dissolved in lactated Ringer's solution (20 ml/kg) was infused into 34 mongrel dogs over a period of 1 hour under pentobarbital anesthesia and changes in hemodynamic and humoral variables were monitored during its infusion and for 3 hours after its infusion. BP elevation during volume loading (from 114 +/- 3 to 128 +/- 3 [SEM] mm Hg) was attributed to an increase in cardiac output. After volume loading, some dogs maintained BP elevation whereas others did not. The former group showed an increase in total peripheral resistance, demonstrating a transformation of cardiac output to total peripheral resistance as a responsible factor in maintenance of the elevated BP. The plasma levels of norepinephrine, vasopressin, and plasma renin activity were not elevated, indicating that these vasoactive factors were not responsible for elevation of the BP or total peripheral resistance. The changes in the hematocrit, atrial natriuretic factor, urine volume, and urinary sodium excretion were identical in the two groups, and natriuresis was not prominent when total peripheral resistance was high. Pressor responses to norepinephrine and angiotensin II were potentiated 3 hours after stopping infusion in both groups, but this potentiation was not correlated with the increase in total peripheral resistance or mean BP. Thus, acute volume expansion produced resistance-dependent hypertension following the initial volume-dependent hypertension. It is unlikely that a vascular sensitizing natriuretic factor plays a role in the resistance-dependent BP elevation. The mechanism and physiological importance of hypersensitivity to vasoactive substances remain to be elucidated.

Hemodynamic parameters were studied before and after rapid dextran infusion in 34 men including 17 patients with sustained essential hypertension and 17 normotensive controls. In both groups of patients, dextran infusion induced a significant increase (p less than 0.001) in central venous pressure (CVP), cardiac output (CO), and stroke volume. The percent change in stroke volume was significantly higher in hypertensives (p less than 0.001) than in controls. Three indices of volume expansion were calculated: 1) the ratio between the change in CO and the change in volume, which was significantly higher in hypertensives (p less than 0.025), 2) the ratio between the change in CO and the change in CVP, which was similar in both groups, and 3) the ratio between the change in volume and the change in CVP, which was significantly reduced in hypertensives (p less than 0.001). In the overall population, the latter ratio was negatively correlated with the change in CO (or in stroke volume) induced by expansion ( r = -0.75). The results provided evidence that: 1) the slope of the relationship between CO and blood volume was steeper in hypertensives than in normotensives, and 2) the steeper slope was due to a reduction in the effective compliance of the vascular bed, causing a greater elevation in CO per unit rise in volume.