The sympathetic nervous system: the muse of primary hypertension.

Von Euler characterised the sympathetic neurotransmitter noradrenaline (NA) and postulated that excessive neural tone was a cause of primary hypertension (PH). Thirty years ago, we found raised NA levels in 30-40% of young patients with PH. Laragh found plasma renin activity (PRA) a risk marker for coronary artery disease. With Esler, Miura, and Campese, a close association was found of plasma NA with PRA. We found raised tyrosine hydroxylase activity (AC) in the hearts of a rabbit model of sinoaortic denervated hypertension and in PH with raised plasma NA. Esler utilised titrated NA infusion and described increased spillover of NA from heart, kidney and subcortical areas of brain of patients with PH. With Eide we found raised cerebrospinal fluid (CSF) NA in PH (not secondary hypertension) and with Kolloch and Miura, we found raised plasma/CSF NA in conjunction with reduced dopaminergic tone. With Shkvatsabaya, Yurenev and Davison, we found that relaxation therapy improved the anger ambience and blood pressure of PH with raised plasma NA vs those with normal NA levels. Campese found a hypothalamic source of raised blood pressure in two rat models - microphenol treated and ischaemic kidney. The resulting hypertension was associated with raised NA turnover of their hypothalamic centres. Finally, with Hsueh and Hodis, we found raised plasma NA in association with insulin resistance increased left ventricular mass and intimal medial hypertrophy in Mexican-American diabetics and their yet unaffected offspring. Reliable estimates of human sympathetic AC, including levels of plasma NA in the effluent of selected organs and peripheral venous and arterial sites, may eventually be displaced by techniques using genetic analysis and molecular biology. Never the less, the sympathetic nervous system appears to play an important role in the pathogenesis, sequelae and therapy of PH.

Sympatholytic therapy in primary hypertension: a user friendly role for the future.

Effective therapy (Rx) in primary hypertension (PH) for 50 years, has featured sympathetic nervous system (SNS) mechanisms. Ganglionic blockers and reserpine were pre-eminent in the 1940s (mydriasis, ileus, impotence, peptic ulcer). Guanethidine, and in the 1960s clonidine and methyldopa, were step II agents to thiazide Rx in the 1950s. Reserpine depletes brain (depression) and peripheral (PPH) noradrenaline (NA) storage sites, guanethidine depleted NA storage via blockade of reuptake. Venomotor sympathoplegia resulted in postural hypertension. An analogue, metaiodobenzyguandine is used in diagnosis and Rx of pheochromocytoma. Clonidine lowers both central and PPH neuronal NA release via both stimulation of alpha agonist adrenoreceptors (sedation) and specific imadazoline binding sites (IBS). Methyldopa lowers pressure via PPH induced NA release (retrograde ejaculation) and via alphamethyl NA on central alpha-2 receptors (depression). The alpha-2 and alpha-2 receptor antagonists (alphaRA) cause reflex tachycardia and first-dose hypotension. Recently a two-fold incidence of congestive heart failure after alphaRA in treated primary hypertensives question their role in PH. The beta RA, with or absent alphaRA, remain premier since the 1970s due to mortality benefit in systolic dysfunction and post myocardial infarction, certifying the role of the SNS in the pathogenesis and sequelae and Rx of PH. The future includes beta RA, specific IBS agents, angiotensin (AII) RA with avid presynaptic AII affinity and vasopeptidase inhibitiors that raise peptides and suppress SNS.

One-year study of felodipine or placebo for stage 1 isolated systolic hypertension.

Asubstantial number of older hypertensive patients have stage 1 isolated systolic hypertension (systolic blood pressure between 140 and 159 mm Hg and diastolic blood pressure <90 mm Hg), but there are currently no data showing that drug treatment is effective, safe, and/or beneficial. To compare the effects of active treatment compared with placebo on blood pressure, left ventricular hypertrophy, and quality of life among older stage 1 isolated systolic hypertensive patients, a randomized, double-blind, parallel-group, multicenter clinical trial comparing felodipine (2.5, 5, or 10 mg once daily) and matching placebo was performed in 171 patients (49% male, average age 66+/-7 years, with 49% white and 30% Hispanic) with a baseline blood pressure of 149+/-7/83+/-6 mm Hg. During 52 weeks of treatment, patients randomized to active treatment achieved significantly lower blood pressures (137.0+/-11.7/80.2+/-7.6 mm Hg for extended-release felodipine versus 147.5+/-16.0/83.5+/-9.7 mm Hg for placebo, P<0.01 for each), a reduced incidence of left ventricular hypertrophy (7% for extended release felodipine versus 24% for placebo, P<0.04), and improved quality of life (change in Psychological General Well-Being index, 3.0+/-6.8 for extended-release felodipine versus -0.8+/-10.3 for placebo, P<0.01) versus baseline. There were no clinically significant differences between treatments in tolerability or adverse effects. Stage 1 isolated systolic hypertension can be effectively and safely treated pharmacologically. Treatment reduced progression to the higher stages of hypertension, reduced the incidence of left ventricular hypertrophy, and improved an overall measure of the quality of life. Larger and longer studies will be needed to document any long-term reduction in cardiovascular event rates associated with treating stage 1 systolic hypertension.

Elevated blood pressure in subjects with lipodystrophy.

OBJECTIVES: To assess the prevalence of elevated blood pressure in patients with lipodystrophy. DESIGN: Case-control study. PARTICIPANTS: Forty-two patients with abnormal body fat (100%) and serum lipids (86%) (HIV-positive cohort) were matched by age and sex to 42 HIV-positive controls without previously diagnosed lipodystrophy and to 13 HIV-negative controls. SETTING: Tertiary care, university-based, fully dedicated HIV clinic. MAIN OUTCOME MEASURES: Frequency and magnitude of elevated blood pressure during highly active antiretroviral therapy. RESULTS: There were 23 +/- 16 and 22 +/- 12 blood pressure measurements recorded per subject over 21 +/- 11 and 22 +/- 11 months for the HIV-positive cohort and HIV-positive controls, respectively. Three or more elevated readings occurred in 74% of the cohort and in 48% of the HIV-positive controls (P = 0.01) and accounted for 38 +/- 25% versus 22 +/- 26% (P = 0.01) of the total readings, respectively. The average of the three highest systolic readings (153 +/- 17 versus 144 +/- 15 mmHg; P = 0.01) and diastolic readings (92 +/- 10 versus 87 +/- 9 mmHg; P = 0.01) was greater for the cohort than for the HIV-positive controls. Family history of hypertension was more common in the cohort than in the controls but accounted for only 13% of the log odds ratio value for elevated blood pressure in the cohort. Systolic blood pressure was correlated with waist-to-hip ratios in the cohort (r = 0.45; P = 0.003) but not in the HIV controls (r = 0.06; P = 0.68) and tended to be related to fasting triglycerides (r = 0.34; P = 0.052) in subjects with HIV. CONCLUSIONS: Elevated blood pressure may be linked to the metabolic disorders occurring in patients with HIV, as in the dysmetabolic syndrome.

Reliability of echocardiographic assessment of left ventricular structure and function: the PRESERVE study. Prospective Randomized Study Evaluating Regression of Ventricular Enlargement.

OBJECTIVES: The study was done to evaluate reliability of echocardiographic left ventricular (LV) mass. BACKGROUND: Echocardiographic estimation of LV mass is affected by several sources of variability. METHODS: We assessed intrapatient reliability of LV mass measurements in 183 hypertensive patients (68% men, 65 +/- 9 years) enrolled in the Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement (PRESERVE) trial after a screening echocardiogram (ECHO) showed LV hypertrophy. A second ECHO was repeated at randomization (45 +/- 25 days later). Two-dimensional (2D)-guided M-mode or 2D linear measurements of LV cavity and wall dimensions were verified by one experienced reader. RESULTS: Mean LV mass was similar at first and second ECHO (243 +/- 53 vs. 241 +/- 54 g) and showed high reliability as estimated by intraclass correlation coefficient (RHO) = 0.93. Within-patient 5th, 10th, 90th and 95th percentiles of between-study difference in LV mass were -32 g, -28 g, +25 g and +35 g. Mean LV mass fell less from the first to the second ECHO than expected from a formula to predict regression to the mean (2 +/- 19 vs. 17 +/- 12 g, p < 0.001). Reliability was also high for LV internal diameter (RHO = 0.87), septal (RHO = 0.85) and posterior wall thickness (RHO = 0.83). Substantial or moderate reliability was observed for measures of LV systolic function and diastolic filling (RHO from 0.71 to 0.57). CONCLUSIONS: Left ventricular mass had high reliability and little regression to the mean; between-study LV mass change of +/-35 g or +/-17 g had > or = 95% or > or = 80% likelihood of being true change.

Relations of diastolic left ventricular filling to systolic chamber and myocardial contractility in hypertensive patients with left ventricular hypertrophy (The PRESERVE Study).

Abnormalities of left ventricular (LV) diastolic filling and stress-corrected midwall shortening (MWS) have been described in hypertensive patients with normal ejection fraction (EF). However, whether stress-corrected MWS parallels LV diastolic filling better than EF does remains uncertain. Blood pressure, body mass index, echocardiographic LV mass and LV geometry, EF and stress-corrected MWS, LV diastolic filling (peak E- and A-wave velocities, E-wave deceleration time, and atrial filling fraction) were evaluated in 212 hypertensive patients with LV hypertrophy enrolled in the Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement study. LV structure, geometry, as well as LV diastolic filling, were compared between patients with reduced EF (<55%, n = 39, 18%) and those with normal EF (>55%) as well as between patients with reduced stress-corrected MWS (<89.2%, n = 31, 15%) and those with normal stress-corrected MWS (>89.2%). Patients with reduced EF had higher LV mass, eccentric LV geometry, and higher heart rate than those with normal EF, although they did not differ in age, blood pressure, or body mass index. LV filling pattern was also similar in those 2 groups. Patients with reduced stress-corrected MWS had higher atrial filling fraction, body mass index, heart rate, LV mass, and concentric geometry than those with normal stress-corrected MWS. Atrial filling fraction was negatively associated with stress-corrected MWS, but not with EF in multivariate models, independently of age, gender, heart rate, and body mass index. Thus, in hypertensive patients with LV hypertrophy, abnormal LV diastolic filling is more closely related to impaired myocardial contractility than to LV chamber EF.

Low-dose combination therapy as first-line hypertension treatment for blacks and nonblacks.

To assess the efficacy and safety of bisoprolol/6.25-mg hydrochlorothiazide (HCTZ), amlodipine, and enalapril in black and nonblack patients, data from two comparative studies were pooled and subgroup analyses performed. Both studies had similar designs and included all three active treatments. The second study also included a placebo group. Subjects (n = 541) with a sitting diastolic blood pressure of 95-114 mmHg were titrated to achieve a diastolic blood pressure < or = 90 mmHg. The studies included 114 blacks and 427 nonblacks. Results of an intention-to-treat analysis of mean change from baseline after 12 weeks of treatment showed the following: 1) blood pressure was significantly lowered by all three active drugs compared with baseline or placebo; 2) in blacks, bisoprolol/6.25-mg HCTZ resulted in significantly greater reductions of systolic and diastolic blood pressure than enalapril or placebo, but was not significantly different from amlodipine; 3) in nonblacks, bisoprolol/6.25-mg HCTZ resulted in significantly greater reduction of diastolic blood pressure than amlodipine, enalapril, or placebo. The placebo-corrected change in blood pressure was greater for blacks than whites on the bisoprolol/6.25-mg HCTZ combination, but this was not statistically significant. Bisoprolol/6.25-mg HCTZ controlled diastolic blood pressure to < or = 90 mmHg in significantly more patients than enalapril or placebo in blacks and nonblacks. The difference in control rates was not significant versus amlodipine. The incidence of drug-related adverse events was similar between treatments; however, bisoprolol/6.25-mg HCTZ had a lower discontinuation rate due to lack of blood pressure control or adverse experiences in both blacks and nonblacks.

Effective dose range of candesartan cilexetil for systemic hypertension. Candesartan Cilexetil Study Investigators.

The results of this randomized, double-blind, placebo-controlled, forced-dose titration study in a diverse population of hypertensive patients in the US indicate that candesartan cilexetil has clinically meaningful dose-related blood pressure-lowering effects and that maximum blood pressure reduction is achieved with doses of 16 and 32 mg given once daily. This study confirms that candesartan cilexetil is a highly effective antihypertensive agent with an excellent tolerability and safety profile, without dose-related adverse effects.

Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy.

BACKGROUND: The degree of proteinuria in patients with diabetes correlates strongly with both an increase in progression of nephropathy as well as cardiovascular events. Moreover, post hoc analyses of recent clinical trials support the concept that reductions of blood pressure and proteinuria correlate with a slowed progression of nephropathy. Both angiotensin converting enzyme (ACE) inhibitors and the nondihydropyridine calcium antagonists, (non-DHPCAs) reduce both arterial pressure and proteinuria in those with diabetic nephropathy. METHODS: The present randomized, open label, parallel group designed study tests the hypothesis that, at similar levels of blood pressure, the combination of an ACE inhibitor, trandolapril (T) with the non-DHPCA, verapamil (V) produces a greater reduction in proteinuria over either agent alone at one year. Thirty-seven participants, mean age 59.6 +/- 5.8 years, with nephropathy (baseline creatinine 1.4 +/- 0.3 mg/dl and proteinuria of 1342 +/- 284 mg/dl) secondary to type 2 diabetes completed the study. Doses of drug were titrated in each group over eight weeks to achieve a goal blood pressure of < 140/90 mm Hg. All participants were counseled to ingest a sodium diet of < 120 mEq/day. RESULTS: Proteinuria reduction from baseline was significantly greater in the T+V group compared to either T alone (-33 +/- 8%, T vs. -62 +/- 10%, T+V; P < 0.001) or V alone (-27 +/- 8%, V vs. -62 +/- 10%, T+V; P < 0.001). No significant differences in either glomerular filtration rate, arterial pressure, fasting blood glucose or urinary sodium excretion were noted at one year. The mean daily dose of the individual components of T+V (2.9 +/- 0.8 mg, T/219 +/- 21.1 mg V) was significantly lower than the dose of either T alone 5.5 +/- 1.1 mg/day (P < 0.01) or V alone 314.8 +/- 46.3 mg, given in two divided doses (P < 0.01). CONCLUSION: These data support the concept that the combination of an ACE inhibitor with a non-DHPCA reduce proteinuria to a greater extent than either agent alone. This added antiproteinuric effect occurs at lower doses of each drug and is independent of further reductions in arterial pressure. These findings could have ramifications for slowing renal disease progression in patients with nephropathy from type 2 diabetes.

Toward improved antihypertensive therapy with calcium channel blockers.

Outcome trials are the scientific method of determining if an antihypertensive agent really works; and for a therapy to work well, it should reduce mortality. The FDA requires only that blood pressure be controlled safely, but current evidence-based medicine demands answers to the mortality/morbidity question. We need this outcome trial information on all the classes of antihypertensives, including calcium channel blockers. For example, we often rely on surrogate endpoints such as control of blood pressure or control of PVCs. If we treat hypertensives with PVCs using beta-blockers or calcium channel blockers, we may see both control of blood pressure and suppression of PVCs. However, as we learned from the CAST trial with flecainide and encainide, PVCs can be controlled, but mortality may increase. On the other hand, the Lewis trial demonstrated that captopril, an ACE inhibitor, reduced proteinuria, which is another surrogate endpoint in diabetic hypertensives with nephropathy, although blood pressure was controlled with diuretic and conventional therapy. Importantly, captopril also reduced morbidity and mortality without influencing blood pressure. Unfortunately, there are no outcome trials measuring mortality endpoints for most of the antihypertensive agents in use today, especially in patients with uncomplicated hypertension.

Low-dose combination treatment for hypertension versus single-drug treatment-bisoprolol/hydrochlorothiazide versus amlodipine, enalapril, and placebo: combined analysis of comparative studies.

To assess the efficacy and safety of 2.5, 5, and 10 mg bisoprolol/6. 25 mg hydrochlorothiazide (HCTZ), 2.5, 5, and 10 mg amlodipine; and 5, 10, 20, and 40 mg enalapril in subjects (n = 541) with a sitting diastolic blood pressure of 95 to 114 mm Hg, data from two comparative studies were pooled. All drugs were titrated to a diastolic blood pressure 90 mm Hg or less. Both studies were double-blind, randomized, parallel dose escalation trials with similar designs and included three active treatments. The second study also had a placebo group. The mean change from baseline of systolic and diastolic blood pressure for placebo (n = 79) was -0. 1/-2.2 mm Hg; amlodipine (n = 154), -12.4/-10.3 mm Hg; enalapril (n = 155), -9.4/-8.2 mm Hg; and bisoprolol/HCTZ (n = 155), -14.0/-12.0. Overall efficacy analyses documented a statistically significant decrease in sitting diastolic blood pressure for bisoprolol/6.25 mg HCTZ compared with placebo, amlodipine, and enalapril. There was a significant reduction in sitting systolic blood pressure for bisoprolol/6.25 mg HCTZ compared with placebo and enalapril but not amlodipine. Also, there was a significant decrease in sitting heart rate for bisoprolol/6.25 mg HCTZ (-6.2 beats/min) compared with placebo (+0.1 beats/min), amlodipine (+1.2 beats/min), and enalapril (+0.5 beats/min). The control rate (diastolic blood pressure < or = 90 mm Hg) for bisoprolol/6.25 mg HCTZ (66.5%) was significantly better than for placebo (21.8%) and enalapril (47.1%) but not amlodipine (58.4%). Of those patients achieving and maintaining control, 49% of the bisoprolol/6.25 mg HCTZ subjects were on the lowest two doses compared with 30% of the amlodipine and 26% of the enalapril subjects. Percentages of patients reporting at least one drug-related adverse event through week 12 were 27%, 24%, 28%, and 25% for placebo, bisoprolol/6.25 mg HCTZ, amlodipine, and enalapril (not significant). Lower doses of two drugs in fixed combination can provide as good or better blood pressure control compared with higher doses of a single drug with similar tolerability and safety.

Fixed-dose combination therapy with trandolapril and verapamil SR is effective in primary hypertension. Trandolapril Study Group.

We assessed the efficacy of monotherapy with trandolapril, an angiotensin converting enzyme (ACE) inhibitor, and of verapamil slow-release (SR), a calcium antagonist, each in a range of three doses as monotherapy, and in the nine possible combinations of therapy in patients with stage I to III diastolic hypertension. After 4 weeks of single-blind placebo, 746 patients in 39 study centers were randomized to one of the 16 double-blind treatments for 6 weeks (placebo; verapamil SR monotherapy 120, 180, or 240 mg; trandolapril monotherapy 0.5, 2, or 8 mg; and trandolapril/verapamil SR combinations 0.5/120, 0.5/180, 0.5/240, 2/120, 2/180, 2/240, 8/120, 8/180, or 8/240 mg. Both mono- and combination therapies achieved the primary efficacy parameters: lowered supine diastolic blood pressure (at trough) more than placebo, P < .01 (except 0.5 mg trandolapril, 0.5/180 and 2/120 combinations, P < .05, and the 120 mg verapamil SR, P = NS). The therapies yielded a trough to peak ratio of >0.52 and had higher percentages of responders as compared with placebo (P < .01, < .05). Supine systolic blood pressures were lowered more by combination therapy than the respective monotherapies, P < .05, P < .01, except the 8/120 combination. Combination therapy was more effective than monotherapy for sitting diastolic blood pressure, P < .05. The percentage of patients with adverse reactions were similar for mono- and combination therapy. Trandolapril had a greater "apparent" incremental effect on the systolic blood pressure reductions than verapamil SR.

Efficacy of combination therapy with trandolapril and verapamil sr in primary hypertension: a 4 x 4 trial design. The Trandolapril Study Group.

The Joint National Committee V suggested that combination therapy can provide effective blood pressure control in patients with stage I-IV hypertension. This 4 x 4 factorial trial design assessed the efficacy of monotherapy with trandolapril-an ACE inhibitor, and verapamil SR-a calcium antagonist, each in a range of 3 doses as monotherapy, and in combination therapy in patients with stage I-III diastolic hypertension. After a 4-week, single-blind placebo treatment period, 746 patients in 39 study centers were randomized to 1 of the 16 double-blind treatments for 6 weeks (placebo, verapamil SR monotherapy 120, 180, or 240 mg; trandolapril monotherapy 0.5, 2, or 8 mg; and trandolapril/verapamil SR combinations 0.5/120, 0.5/180, 0.5/240, 2/120, 2/180, 2/240, 8/120, 8/180, or 8/240 mg. Both mono and combination therapies achieved the primary efficacy parameters: lowered diastolic blood pressure (at trough) more than placebo, p < 01 (except the 120 mg verapamil SR, NS, 0.5 mg trandolapril, 0.5/180 and 2/120 combinations, p < 05), yielded a trough to peak ratio of > 0.52 and had higher percentages of responders compared to placebo. Combination therapy was more effective than monotherapy for sitting diastolic blood pressure 2/180, p < 01; 2/240 and 8/240, p < 05. There were no differences between active treatment groups and placebo as a percentage of patients having adverse reactions. Trandolapril, 2 and 8 mg, appeared to have a greater incremental effect on the systolic blood pressure reduction of the combination than verapamil SR 180 and 240 mg.

Additional antianginal and anti-ischemic efficacy of mibefradil in patients pretreated with a beta blocker for chronic stable angina pectoris.

This study assessed the safety, tolerability, and efficacy of mibefradil when added to beta-blocker monotherapy in patients with chronic stable angina pectoris. Two hundred five patients were randomized to receive double-blind treatment with either placebo (n = 70), mibefradil 25 mg (n = 67), or mibefradil 50 mg (n = 68) for 2 weeks. Exercise tolerance tests (ETTs) were performed at the end of the run-in (baseline) and double-blind treatment periods, and patients maintained an anginal diary. Compared with placebo, treatment with mibefradil 50 mg resulted in significant increases in exercise duration (36 +/- 51 seconds; p = 0.036), time to onset of angina (48 +/- 65 seconds; p = 0.002), and time to persistent 1-mm ST-segment depression (47 +/- 77 seconds; p = 0.004). Greater reductions in heart rate, blood pressure, and the rate-pressure product were more apparent at each stage of the ETT in the 50-mg mibefradil group than in the placebo group. Daily treatment with mibefradil 50 mg was associated with a significant decrease in the number of weekly anginal attacks (-2.1 +/- 4.0, p = 0.020) compared with placebo. The addition of mibefradil to existing beta-blocker therapy was well tolerated. Dizziness was the most frequently reported adverse event in the mibefradil 50-mg dose, and occurred with an incidence of 4.4%. The addition of mibefradil 50 mg, administered once daily, to patients on stable beta-blocker therapy produced additive antianginal and anti-ischemic effects and was well tolerated.

Equivalent reduction of proteinuria in hypertensives by either nifedipine GITS or enalapril: disparate effects on neurohormones and ambulatory blood pressure and the influence of salt.

OBJECTIVE: We compared the efficacy of two classes of antihypertensive therapy on ambulatory blood pressure control and proteinuria in patients with hypertension. Furthermore, we determined the effects of the interaction of these therapies on neurohormonal activation and of the patients' ambient sodium intake on the outcomes. METHODS: Sustained-release nifedipine (nifedipine gastrointestinal therapeutic system, GITS) 30-120 mg/day was compared in a double-blind sequential randomized placebo-controlled trial with enalapril 5-30 mg/day regarding office and 24-hour blood pressure control, plasma renin activity, noradrenaline and adrenaline levels and 24-hour urinary protein and sodium in 46 elderly nondiabetic hypertensive patients in a 16- to 18-week trial. RESULTS: Both nifedipine GITS and enalapril controlled ambulatory blood pressure during the day and at peak effect. Nifedipine GITS controlled ambulatory blood pressure during the early morning surge and at night time as well. Nifedipine GITS increased plasma renin activity and noradrenaline by 50 and 20%, respectively, compared to the 150 and 0% change produced by enalapril. Both nifedipine GITS and enalapril reduced proteinuria by 37%. Patients had increasing levels or proteinuria proportional to higher ambient sodium intake (r = 0.48; p < 0.01). This effect was accentuated during nifedipine GITS therapy as compared to enalapril. CONCLUSION: Nifedipine GITS was superior to enalapril in controlling ambulatory blood pressure, but they were equivalent in reducing proteinuria (37%). They had disparate effects on neural activation and the duration of action. Raised protein excretion appears to be associated with raised sodium intake. This was apparent especially during nifedipine XL therapy.

A Therapeutic Commentary.

ABSTRACT: Thirty-one million patients in the United States undergo surgical procedures every year. Approximately 10%-the majority of these with hypertension-are at an increased risk for perioperative and postoperative cardiovascular morbidity and mortality. Thus, hypertensive patients requiring surgery, especially the 2.1 million undergoing noncardiac procedures, should be evaluated carefully for the magnitude, and if severe, the cause of the hypertension. Additionally, their associated metabolic and cardiovascular status should be characterized and corrected with aggressive therapy. Hypertensive patients with known ischemic heart disease, those with multiple risk factors for ischemic heart disease (IHD), some with valvular heart disease, and those with congestive heart failure should be evaluated for their ability to perform the physical and social activities of everyday life, and, when necessary, have formal stress testing. Most studies suggest that blood pressures of 180/110 mm Hg or greater are associated with a greater risk for perioperative ischemic events. Therefore, the goals of blood pressure control should be to reduce the blood pressure without jeopardizing organ function. Antihypertensive medication should be administered until the time of surgery. beta-Receptor blockers should be instituted or continued in patients with angina and in some patients with congestive heart failure. Those without prior antihypertensive therapy might be best treated with beta-blocker therapy perioperatively as evidenced by the Multicenter Study of Perioperative Research Group with atenolol and those earlier studies with metoprolol. The risks of the surgery should be discussed with the patient so the risks can be weighed against the expected benefit. Studies suggest that perioperative risk for any patient, and especially patients with hypertension, are in part related to the adrenergic arousal before, during, and after the procedure as evidenced by the rise in heart rate and blood pressure, along with the liberation of clotting facators and increased risk for plaque rupture, coronary vasoplasm, and consequent myocardial infarction and fibrosis.

The impact of ethnicity on response to antihypertensive therapy.

The aim of this review is to assess the prevalence of complications and responses to various antihypertensive drug therapies in ethnic minority groups in the United States. In some instances, these comments are extended to responses of citizens in their countries of origin. The incidence of hypertension, mortality from hypertensive heart disease, stroke, and hypertensive renal disease are higher in African Americans. Although some Hispanic Americans have a lesser risk for hypertension, they have a greater risk for other risk factors such as diabetes and dyslipidemia. There is a similar association between income and mortality for both African Americans and Hispanic Americans. When compared to European Americans and other ethnic minorities, African Americans respond less favorably to beta blockers and angiotensin-converting enzyme (ACE) inhibitors. Nevertheless, the observed response in African Americans to ACE inhibitors and beta blockers is clinically significant. The available literature indicates that Asian American responses to calcium antagonists seem to be more favorable than responses to ACE inhibitors and equivalent to their responses to diuretic and beta blocker therapy. Although there are few published studies of drug efficacy in Hispanic Americans, there appears to be no hierarchy in response to the various antihypertensive drug classes. Ethnicity is not an accurate criterion for predicting poor response to any class of antihypertensive therapy. Thus, there is little justification to use racial profiling as a criterion for the avoidance of selected drug classes because of presumed lack of efficacy. Observed differences in the incidence of hypertension and its poor outcomes have led some investigators to postulate that the etiology of hypertension in ethnic minority groups is intrinsically different from whites. Awareness of racial differences in hypertension outcomes evolved in the United States within a historical context that does not fully appreciate that race is often a surrogate for many social and economic factors that influence health status and healthcare delivery. Poor outcomes in ethnic minority groups occur in many diseases, not only hypertension. The goal of ethnicity-related research should be to describe the diversity of disease expression in humans and to target at-risk groups for prevention and early intervention. The use of racial descriptors to explain genetic differences in ethnic groups should take a lesser priority.

Neural mechanisms in primary hypertension. Efficacy of alpha-blockade with doxazosin during stress.

This single-blind study assessed the role of the sympathetic nervous system in primary hypertensives, at rest and during stress, and examined blood pressure responses to an alpha 1-blocker, doxazosin. Twenty patients were selected who had a sitting diastolic blood pressure 95 to 115 mm Hg at the end of the placebo period. Doxazosin was given in doses of 1 mg per day initially, then increased weekly to 2, 4, 8, and 16 mg, until goal blood pressure or maximum dose was reached or side effects limited further increase. Their determined dose of doxazosin was held constant for 16 weeks of the maintenance period. Mental and isometric stress tests were performed at the end of placebo and at the first and last months of maintenance. Diastolic blood pressures were related to baseline plasma norepinephrine, r = 0.61, P < .01. The dose of doxazosin administered was 8.4 +/- 4.1 mg. After 4 months of therapy, doxazosin lowered blood pressure from 147 +/- 16/99 +/- 3 to 135 +/- 5/87 +/- 8 sitting, and from 146 +/- 14/99 +/- 6 to 130 +/- 14/86 +/- 7 standing, respectively. Heart rates were not changed. The reduction of standing systolic blood pressure was related to baseline norepinephrine in the 12 patients who reached goal blood pressure, r = 0.57, P < .05. During mental and isometric stress tests, the percentage changes of blood pressures were related to their baseline plasma norepinephrine. Doxazosin reduced the percentage increments of blood pressure during mental stress 12.2 +/- 5.7/11.8 +/- 4.3% versus 5.7 +/- 1.0/8.1 +/- 7.4%, P < .01/.05. Doxazosin also blunted the diastolic blood pressure response to isometric exercise from 18.3 +/- 12.2% to 9.3 +/- 11.0%, P < .05. Neurogenic factors participate in the elevation of blood pressure in some patients with primary hypertension. The alpha-blocker doxazosin was effective in 60% of the hypertensive patients--it controlled blood pressure during laboratory stress, suggesting particular value in reduction of blood pressure during ambient stress of everyday living.

Individualization of therapy for hypertension in the 1990's: the role of calcium antagonists.

The Joint National Committee Reports IV (1988) and V (1992) have emphasized individualization of drug therapy for patients with hypertension-a departure from the "stepped" care approach of initiating therapy with diuretics as advocated by the JNC I-III in the 1970's and 1980's. This review highlights individualization or "patient profiling" using calcium channel blockers as first-line treatment strategy for patients with primary hypertension--especially in the patient who has attendant risk factors and sequelae. The calcium channel antagonists, especially effective in elderly and Black patients, have proven efficacy in reducing left ventricular hypertrophy and improving diastolic function in patients with hypertensive heart disease. The heart rate limiting calcium antagonist, verapamil, has been found effective in outcome trials of reducing death and reinfarction rates post myocardial infarction and is an alternative therapy for the beta blocker intolerant hypertensive post myocardial infarction. More vascular specific dihydropyridines (felodipine, isradipine, and amlodipine) may be preferable to rate limiting agents in hypertensives with sinus node or AV conduction disorders and in those with impaired left ventricular systolic function. Verapamil and diltiazem have been effective in preliminary trials in reducing proteinuria and preserving renal function in both diabetic and non diabetic hypertensives. Calcium channel antagonists appear to prevent the progress of atherosclerosis independent of their antihypertensive properties. Further, they have theoretic value in improving endothelial mediated vasodilation.