Management of hypertensive crises: the scientific basis for treatment decisions.

The spectrum of disorders associated with an elevated blood pressure (BP) encompasses chronic uncomplicated hypertension and the hypertensive crises, including hypertensive urgencies and emergencies. Although these syndromes vary widely in their presentations, clinical courses, and outcomes they share pathophysiologic mechanisms and, consequently, therapeutic responses to specifically targeted antihypertensive drug types. Nevertheless, hypertensive crises are often treated with drugs which, in that setting are either unsafe or are of unsubstantiated efficacy. The purpose of this review is to examine the pathophysiology of commonly encountered hypertensive crises, including stroke, hypertensive encephalopathy, aortic dissection, acute pulmonary edema, and preeclampsia-eclampsia and to provide a rational approach to their treatment based upon relevant pathophysiologic and pharmacologic principles. Measurement of plasma renin activity (PRA) level often provides insight regarding pathophysiology and predicts efficacy of antihypertensive treatments in the individual patient. However, in hypertensive crises, drug therapy is initiated before the PRA level is known. Nevertheless, the renin-angiotensin dependence (R-type) or volume dependence (V-type) of hypertension can often be deduced by the BP response to drugs that interrupt the renin system (R-drugs) or that decrease body volume (V-drugs). Based upon these considerations, a treatment algorithm is provided to guide drug selection in patients presenting with a hypertensive crisis.

Abstract, closing summary, and table of contents for Laragh's 25 lessons in pathophysiology and 12 clinical pearls for treating hypertension.

These 25 lessons 1) review the roles of plasma renin levels for causing malignant and most essential hypertension and their related vascular injuries (heart attack, heart failure, kidney failure and stroke); 2) review how antihypertensive anti-R drugs that block renin activity (beta blockers, the first converting enzyme inhibitor from venom, and the first angiotensin receptor blocker) were used to reveal plasma renin involvement in the hypertension of medium and high renin patients and to show; 3) that the 30% with low renin essential hypertension do not respond to R drugs, are not prone to heart attack or stroke, and BP is corrected instead by the natriuretic anti-V drugs (diuretics, spironolactone, CCB, alpha blockers); 4) thus, all hypertensives can be divided into R patients who have too much renin vasoconstriction or V patients who instead have predominant sodium-volume mediation. Furthermore, all antihypertensive drug classes can be divided into R drugs that block the renin factor, or V drugs that reduce body sodium volume; 5) these findings document our conception of two biochemically and physiologically different final factors that sustain all BP in which the sodium-volume factor continuously sustains cardiac output and flow while plasma renin-angiotensin sets total peripheral resistance (TPR), which, within the Poiseuille Equation (BP = cardiac output [CO] x TPR) describes our [Na+-volume x renin-angiotensin vasoconstriction] model that supports all normotension or hypertension; 6) in this light, we designed a visit-by-visit method for treating untreated hypertensives using the ambient plasma renin level and BP responses to guide primary drug therapy against either the V or R factor; and 7) for also correcting nonresponders receiving multiple drugs where renin testing correctly guides addition or subtraction of drugs depending on whether the test indicates unresponsiveness due to a reactive sodium-volume excess, or to lack of effectiveness of an R drug in a V patient or of a V drug in an R patient, or from large reactive increases in renin that override the R drug, calling for strengthening the R and/or removing V drugs. This objective, biochemically based method results in effective longterm BP control of nearly all patients using fewer, but the correct drug(s) for each individual.

Plasma renin activity in the emergency department and its independent association with acute myocardial infarction.

Elevated plasma renin activity (PRA) is associated with increased risk of future myocardial infarction (MI) in ambulatory hypertensive patients. The present study evaluated the relationship of PRA to the diagnosis of acute MI in patients presenting to an emergency department with suspected acute MI. PRA was measured upon entry to the emergency department, before any acute treatment, as part of the standard evaluation of 349 consecutive patients who were hospitalized for suspected MI. Diagnosis of acute MI was confirmed in 73 patients, and ruled out in 276. They did not differ in age (65.9 +/- 2 v 66.1 +/- 1 years), systolic (143 +/- 4 v 140 +/- 2 mm Hg), or diastolic (81 +/- 2 v 81 +/- 1 mm Hg) pressures. Median PRA was 2.7-fold higher in acute MI (0.89 v 0.33 ng/L/s; P < .001). In a multivariate analysis controlling for other cardiac risk factors and prior drug therapy, PRA as a continuous variable was the predominant independent factor associated with acute MI (P < .0001), followed by white race (P = .002) and history of hypertension (P = .047). The height of the PRA level upon entry to the emergency department was directly and independently associated with the diagnosis of acute MI. These new findings extend earlier reports because they encompass acute MI patients, include both hypertensive and normotensive patients, and control for potentially confounding variables. Based on these observations, a randomized clinical trial is warranted to determine whether measurement of PRA in acute MI could refine the process by which treatments are applied.

Delayed recovery of hypertension after single dose losartan in angiotensin II-infused conscious rats.

OBJECTIVE: In a conscious unrestrained rat model, it takes approximately 1 week for angiotensin II to increase blood pressure to maximum levels. We investigated the time required for hypertension to fully recover after acute angiotensin II receptor blockade in this angiotensin II dependent hypertensive model. DESIGN: Conscious unrestrained rats (n = 8) infused with 10 ng/kg per min angiotensin II for 21 days received losartan (10 mg/kg) on day 17 of angiotensin II infusion. Mean arterial pressure (MAP) and heart rate were monitored continuously. The acute pressor response to 50 ng/kg per min angiotensin II was monitored for 2 h on days 15, 17, 18, 19 and 20 of angiotensin II infusion. Plasma renin concentration (PRC) was measured daily. RESULTS: Angiotensin II increased MAP acutely by 26 +/- 2 mmHg and by a further 23 +/- 4 mmHg between days 4 and 8. Losartan acutely reduced MAP by 75 +/- 2 mmHg; 24 h later MAP had partially recovered but remained suppressed by 47 +/- 3 mmHg. MAP had not fully recovered 4 days later. Some 2 h after losartan, the acute pressor response to angiotensin II had fallen from 24 +/- 2 mmHg to zero. This recovered to 13 +/- 5 and 28 +/- 2 mmHg 24 and 48 h post losartan. After losartan PRC rose from 0.1 +/- 0.05 to above 1 ng/ml per h for less than 24 h. CONCLUSION: A single dose of losartan reverses both the fast and slow pressor effects of continuous angiotensin II infusions. While losartan is metabolized, the fast vasoconstrictor effect recovers quickly but the slow pressor effect takes almost a week to build up again to maximum levels. Since the slow pressor effect is mediated via the AT1 receptor, any means of blocking the renin-angiotensin system is likely to keep blood pressure below maximum hypertensive levels for several days after the drug has disappeared from the circulation.

Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects.

Although beta-adrenergic-blocking drugs suppress the renin system (RAAS), plasma angiotensin II (Ang II) responses during beta-blockade have not been defined. This study quantifies the effects of beta-blockade on the RAAS and examines its impact on prorenin processing by measuring changes in the ratio of plasma renin activity (PRA) to total renin. In normotensive (N = 14) and hypertensive (N = 16) subjects, blood pressure (BP), heart rate, PRA, plasma prorenin, plasma total renin (prorenin + PRA), ratio of PRA to total renin (%PRA), plasma Ang II, and urinary aldosterone were measured before and after 1 week of beta-blockade. Plasma renin activity, Ang II, and urinary aldosterone levels were similar for normotensive and hypertensive subjects. Plasma renin activity correlated with Ang II. Total renin, which is proportional to (pro)renin gene expression, was lower in hypertensive subjects and was inversely related to BP. Beta-blockade decreased BP and heart rate in both groups, with medium- and high-renin hypertensive subjects responding more frequently than those with low renin. Beta-blockade consistently suppressed PRA, Ang II, and aldosterone. Total renin was unchanged, thus, %PRA fell. These results indicate that beta-blockers suppress plasma angiotensin II levels, in parallel with the marked reductions in PRA and urinary aldosterone levels in normotensive and hypertensive subjects. The suppression of Ang II levels was comparable to that produced during angiotensin converting enzyme (ACE) inhibition. However, by reducing prorenin processing to renin, beta-blockers do not stimulate renin secretion, unlike ACE inhibitors and Ang II receptor antagonists. This unique action of beta-blockers has important implications for the treatment of cardiovascular disease.

Appropriate regulation of renin and blood pressure in 45-kb human renin/human angiotensinogen transgenic mice.

The renin-angiotensin system is normally subject to servo control mechanisms that suppress plasma renin levels in response to increased blood pressure and increase plasma renin levels when blood pressure falls. In most species, renin is rate limiting, and angiotensinogen circulates at a concentration close to the Km, so varying the concentration of either can affect the rate of angiotensin formation. However, only the plasma renin level responds to changes in blood pressure and sodium balance to maintain blood pressure homeostasis. Therefore, the high plasma human renin levels and the hypertension of mice and rats containing both human renin and angiotensinogen transgenes indicate inappropriate regulation of renin and blood pressure. These anomalies led us to develop new lines of transgenic mice with a longer human renin gene fragment (45 kb) than earlier lines (13 to 15 kb). Unlike their predecessors, the 45-kb hREN mice secrete human renin only from the kidneys, and both the human and mouse renins respond appropriately to physiological stimuli. To determine whether blood pressure is also regulated appropriately, we crossed these new 45-kb hREN mice with mice containing the human angiotensinogen gene. All doubly transgenic mice were normotensive like their singly transgenic and nontransgenic littermates. Moreover, among doubly transgenic mice, both human and mouse plasma renin concentrations were suppressed relative to the singly transgenic 45-kb hREN mice. These findings demonstrate the importance of appropriate cell and tissue specificity of gene expression in constructing transgenic models and affirm the pivotal role played by renal renin secretion in blood pressure control.

Kidney is the only source of human plasma renin in 45-kb human renin transgenic mice.

Prorenin is expressed in certain extrarenal tissues, but normally only the kidneys process prorenin to renin and secrete renin into the circulation. Although transgenic animal lines containing the human renin (hREN) structural gene with either 0.9-kb or 3-kb 5'-flanking DNA express the transgene appropriately in renal juxtaglomerular cells and secrete hREN into the circulation, the source of the circulating renin is not known. In the present study, we observed that 13-kb hREN transgenic mice that contain the structural gene and 0.9-kb 5'-flanking DNA express hREN mRNA in many unusual tissues. We also observed that circulating hREN levels in 13-kb hREN mice increased after bilateral nephrectomy. These results suggested that the hREN gene is expressed at inappropriate locations where prorenin might be processed to renin. To determine if more distal sequences flanking the hREN gene might contribute to cell and tissue specificity, we used a 45-kb hREN genomic fragment that contained the structural gene and about 25-kb 5'- and 8-kb 3'-flanking DNA sequences to generate 3 separate transgenic lines that contained the intact transgene sequences. Ribonuclease protection assays revealed a much narrower tissue distribution of hREN expression than in the 13-kb hREN transgenic mice. In each 45-kb hREN line, hREN mRNA was present only in the kidney, adrenal, lung, eye, ovary, and brain. Moreover, 24 hours after nephrectomy, human plasma renin fell to very low levels, indistinguishable from those of nontransgenic littermates, indicating that their circulating hREN is of renal origin. These studies suggest that sequences flanking the structural gene, missing from previous hREN transgenic lines, suppress renin gene expression at inappropriate extrarenal sites where cellular proteases, to which prorenin is not normally exposed, could convert prorenin to renin, resulting in abnormal secretion of renin into the plasma.

Identical hemodynamic and hormonal responses to 14-day infusions of renin or angiotensin II in conscious rats.

OBJECTIVE: To investigate whether plasma angiotensin II (Ang II) determines the effects of the renin-angiotensin system or whether tissue uptake of renin and localized production of Ang II might account for any cardiovascular, renal, hormonal or drinking effect of circulating renin. DESIGN: Intravenous infusions of renin (0.6 ng/min; n = 10) and Ang II (3.5 ng/min; n = 10) that produce similar plasma Ang II levels were compared for 2 weeks with vehicle (n = 7) in conscious rats after a 1-week control period. Mean arterial pressure (MAP) and the heart rate were measured continuously. Hormones and renal function were measured twice weekly. Plasma Ang II and recovery data were measured in seven additional rats. RESULTS: In renin- and Ang II-infused rats, respectively, plasma Ang II increased similarly from 4.5 +/- 0.8 and 4.4 +/- 0.9 to 10.8 +/- 0.7 and 10.6 +/- 0.7 pg/ml and declined similarly in the second week to 7.0 +/- 1.1 and 7.0 +/- 1.5 pg/ml. Plasma renin increased from 4.2 +/- 0.7 to 21.7 +/- 1.3 and fell from 5.9 +/- 0.5 to 0.6 +/- 0.2 ng/ml per h respectively. Plasma prorenin fell similarly (> 70%); angiotensinogen was unchanged. MAP rose initially by 25.6 +/- 1.2 and 23.3 +/- 0.9 mmHg and by an additional 21.1 +/- 2.4 and 27.4 +/- 1.8 mmHg on days 5-8. The heart rate fell gradually but transiently by -11% in both. Although the initial MAP rise was slower in renin-infused rats (P< 0.05) MAP returned to baseline within 2 h after both infusions were stopped. Changes in renal vascular resistance, renal blood flow, glomerular filtration rate, urinary sodium, potassium and water excretion and water intake were not significantly different between renin- and Ang II-infused rats. CONCLUSIONS: Intravenous infusions of low doses of renin or Ang II into conscious rats increase MAP identically. MAP increases in two phases 5-8 days apart, in coordination with transient falls in the heart rate. Renin- and Ang II-induced chronic hypertension are identically sustained by very small increases in plasma Ang II. Blood pressure increases more slowly with renin infusions, consistent with tissue binding. Notwithstanding, no evidence was obtained for a physiological role of tissue-bound renin in causing the cardiovascular, renal, hormonal and drinking responses measured in this study.

Appropriate regulation of human renin gene expression and secretion in 45-kb human renin transgenic mice.

To create physiological models of the human renin-angiotensin system in transgenic animals, the component genes should be expressed in the correct tissues and cells and respond appropriately to physiological stimuli. We recently showed that mice carrying a 45-kb human renin genomic fragment, containing approximately 25 kb 5'-flanking DNA and 6 kb 3'-flanking DNA, express the transgene in a highly cell- and tissue-specific pattern. More importantly, in contrast to previous models, human renin in the circulating plasma of these mice is derived exclusively from the kidneys. In the present study, we tested the responses of both human and mouse renal renin expression and secretion of the 45-kb hREN transgenic mice to a variety of physiological and pharmacological stimuli. A sodium-deficient diet, angiotensin-converting enzyme inhibition, and beta1-adrenergic stimulation each increased both human and mouse plasma renin concentration significantly, whereas elevated blood pressure and/or increased plasma angiotensin II levels suppressed them. Human and mouse renal renin mRNA levels changed similarly but to a lesser degree. These studies demonstrate that human renin synthesis and secretion respond appropriately in 45-kb hREN mice to physiological stimuli. This most likely results from appropriate cell-specific expression of the transgene conferred by the extended transgene flanking sequences.

Serum sex hormone levels in postmenopausal women with hypertension.

In order to test the hypothesis that an alteration in the sex hormone milieu may underlie risk factors for myocardial infarction, fasting serum sex hormones, ie, estradiol, testosterone, free testosterone, and androstenedione, were measured in 24 hypertensive and in 19 healthy postmenopausal women. The mean serum free testosterone level (P=0.01) and the free-to-total testosterone ratio (P < 0.04) were increased in the women with hypertension. In a stepwise multiple regression analysis on the hypertensive and normotensive groups combined, with systolic blood pressure (SBP) as the dependent variable and body mass index, age, free testosterone, estradiol, insulin, and cholesterol levels as the independent variables, only free testosterone showed an independent relationship to SBP (P=0.009). The finding in the present study of an independent positive relationship of free testosterone with hypertension is consistent with a similar relationship of free testosterone with other risk factors for myocardial infarction in women found in previous studies and supports the hypothesis.

Usefulness of subnormal midwall fractional shortening in predicting left ventricular exercise dysfunction in asymptomatic patients with systemic hypertension.

We have recently shown that a subgroup of asymptomatic hypertensive patients exhibit subnormal left ventricular (LV) midwall fiber shortening at rest and that this finding predicts morbidity and mortality independently of age, blood pressure (BP), or the presence of LV hypertrophy. However, it is unknown whether abnormal midwall fractional shortening predicts either subnormal LV functional reserve or extracardiac damage in asymptomatic hypertensive patients. Accordingly, we compared radionuclide cineangiographic LV ejection fraction at rest and maximum exercise as well as clinical findings between 89 patients with normal and 16 patients with subnormal midwall fractional shortening by echocardiogram. Patients with low midwall fractional shortening were similar in gender, age, and systolic BP to those with normal shortening but had higher mean diastolic BP and body mass indexes (both p < 0.05). The 2 groups also had similar resting ejection fraction (56 +/- 9% vs 55 +/- 15%, with normal or subnormal shortening, respectively, p = NS). Patients with subnormal midwall fractional shortening had higher LV mass and tended to have higher urinary protein excretion and serum creatinine levels. Subnormal LV ejection fraction with exercise (< 54%) was observed in 13 of 89 patients (15%) with normal midwall fractional shortening but in 7 of 16 patients (44%) with subnormal shortening (p < 0.05). Multiple linear regression analysis revealed that midwall fractional shortening independently predicted exercise performance (p < 0.001). Thus, subnormal midwall fractional shortening predicts depressed LV fractional reserve in asymptomatic hypertensive patients and may contribute to identification of patients with extracardiac target-organ damage.

Plasma renin activity: a risk factor for myocardial infarction in hypertensive patients.

To determine whether pretreatment plasma renin activity (PRA), without accompanying 24-h urine sodium, can predict myocardial infarction (MI), the PRA levels of 2,902 hypertensive patients [white (38%), male (65%), median age 55 years], with mean entry blood pressure (BP) of 150/97 mm Hg were examined. During an average 3.6 years follow-up (87% > or = 9 months), there were 55 MIs, 21 strokes, and 16 other cardiovascular disease (CVD) deaths. Classification of PRA levels into 3 renin strata [high (H) PRA > or = 4.5 (n = 354), normal (N) 0.75 to 4.49 (n = 1,622), and low (L) < 0.75 (n = 926) ng/mL/h] yielded subgroups that did not differ in LVH (9% v 11%) or smoking prevalence (26% v 25%) but high versus low PRA subjects included more aged < 55 years (64% v 53%); white (49% v 25%); men (79% v 52%); cholesterol > or = 6.3 mmol/L (33% v 25%); all P values < .01. MI rates per 1,000/year were H: 9.3, N: 5.5, L: 2.5 (H v L, RR = 3.8, 95% CI: 1.7 to 8.4). A similar relationship was seen with total CVD (H: 12.5, N: 9.3, L: 5.2; RR = 2.4, 95% CI: 1.3 to 4.5) and all-cause mortality (H: 7.0, N: 6.2, L: 2.5; RR = 2.8, 95% CI: 1.2 to 6.8) but not CVA (H: 1.6, N: 2.0, L: 1.9). In a Cox survival analysis only renin, age, sex, smoking, LVH, and cholesterol were significantly (P < .02) related to MI occurrence. There was, for every 2 unit increase in PRA, an overall 25% increase in MI incidence. Among hypertensive subjects, PRA level (without urine sodium), is independently and directly associated with the incidence of MI.

Chronic carvedilol reduces mortality and renal damage in hypertensive stroke-prone rats.

The effects of carvedilol, a novel vasodilating beta-blocker and antioxidant, and propranolol on survival, neurobehavioral deficits, cardiovascular parameters, plasma renin, plasma aldosterone levels and renal pathology were determined in stroke-prone spontaneously hypertensive rats. Stroke-prone spontaneously hypertensive rats were allowed access to 1% NaCl as the drinking solution and a high fat diet supplemented with carvedilol (1200 or 2400 ppm) or propranolol (2400 ppm). The control group consisted of stroke-prone spontaneously hypertensive rats placed on the same diet with no drug supplement. Animals fed propranolol had a blood level of 864 +/- 68 ng/ml, whereas carvedilol-fed animals had blood levels of 24 +/- 4 ng/ml at 1200 ppm and 471 +/- 145 ng/ml at 2400 ppm. Carvedilol and propranolol treatment resulted in significant beta adrenoceptor blockade. Both compounds reduced heart rate, but had no significant effects on systolic arterial blood pressure. Carvedilol- and propranolol-treated animals also exhibited significant, prolonged protection from neurobehavioral deficits and mortality (P < .01). Elevated plasma renin activity and aldosterone levels seen in untreated controls were significantly decreased by propranolol (P < .05), and to a considerably greater extent by the same dose of carvedilol (P < .01). Carvedilol decreased renal histopathological damage and cardiac hypertrophy to a greater extent (P < .01) than propranolol (at equal doses). Both carvedilol (P < .01)- and propranolol (P < .01)-treated animals had considerably reduced renal damage at 18 weeks of treatment. Carvedilol reduced renal damage more than propranolol (P < .05). In addition, the lower (1200 ppm) dose of carvedilol, which decreased neurobehavioral deficits and mortality, had no significant effects on organ mass or renal function, but significantly (P < .01) reduced renal damage. These data indicate that both beta adrenoceptor blockers, especially carvedilol to a considerably greater degree, convey significant protection in a genetic model of severe hypertension that results in renal and cardiovascular organ pathology, neurobehavioral deficits and premature death.

Influence of obesity on left ventricular midwall mechanics in arterial hypertension.

The evaluation of the effect of obesity on left ventricular systolic performance may differ in relation to the method used to measure left ventricular function and to the type of study population. Whether obesity worsens left ventricular midwall mechanics in arterial hypertension has never been investigated. Accordingly, we assessed echocardiographic left ventricular midwall shortening-circumferential end-systolic stress relations in 156 normotensive and normal-weight (reference) adults, 94 normotensive and overweight (1985 National Institutes of Health partition values) to obese (body mass index > 30 kg/m2) adults, 263 hypertensive and normal-weight adults, and 224 hypertensive and overweight-to-obese adults. There was an inverse relation of midwall shortening to circumferential end-systolic stress in all groups (all P < .005). Left ventricular performance as a ratio of observed to predicted midwall shortening fell below the fifth percentile in 4 of 94 (4%) of overweight-to-obese normotensive individuals. Eighty-eight of 487 hypertensive subjects (18.1%) exhibited depressed midwall shortening as a percentage of the value predicted from wall stress, with no difference between normal-weight (50 of 263 [19%]) and overweight (38 of 224 [17%]) subjects. Sixty-one normotensive and 131 hypertensive subjects were frankly obese. After adjustment for sex and age, midwall shortening, as either absolute values or a percentage of predicted, was not statistically different among obese, overweight, and normal-weight subjects in both normotensive and hypertensive groups. For each quartile of observed-to-predicted midwall shortening ratio, obese subjects had greater left ventricular end-diastolic volume than normal-weight subjects among both normotensive and, more evidently, hypertensive subjects. A predicted midwall shortening was generated from both wall stress and left ventricular volume with the use of multiple regression analysis. High body mass index, mean blood pressure, aging, and male sex independently predicted low afterload and left ventricular volume-independent midwall left ventricular performance (multiple R = .31, P < .0001). Thus, (1) midwall left ventricular systolic performance in asymptomatic overweight or frankly obese individuals is comparable to that in normal-weight individuals in both the presence and absence of arterial hypertension; (2) however, maintenance of normal life ventricular performance in obese individuals is associated with the use of Starling reserve; and (3) this compensatory mechanism is especially evident when arterial hypertension and obesity coexist.