Reducing cardiovascular disease risk with diet.

OBJECTIVE: Past research efforts to determine the influence of the diet on cardiovascular (CV) health have focused on the individual roles of specific dietary components with debatable success. Awareness of the impact and complexity of nutrient interactions has expanded in recent years to include assessment of dietary patterns as they contribute to lower CV disease risk. RESEARCH METHODS AND PROCEDURES: In a series of multicenter studies, we compared a comprehensive, prepared meal plan, formulated to meet recommended intake levels of macro- and micronutrients, with a self-selected diet based on the exchange system. The three studies comprised adult participants with hypertension, hyperlipidemia, and type 2 diabetes (n = 560, 251, and 330, respectively). The first two studies (10 weeks) varied by the amount of contact with study personnel, and the third study assessed long-term effects over 52 weeks. Outcome measures included: blood pressure, lipid and lipoprotein levels, glycemic control, homocysteine, compliance, quality of life, and weight. RESULTS: The first study demonstrated significant improvements in all measures, with greater improvements with the prepared meal plan compared with the self-selected diet. The second study, designed to parallel the contact frequency that would occur in a real world clinical setting, also produced significant improvements in multiple CV risk factors. In the long-term study, in addition to sustained improvements in risk factors, significant weight loss was achieved and maintained over the 52 weeks. DISCUSSION: These trials demonstrate that regular consumption of a nutritionally complete diet offers multiple, concurrent clinical benefits for reducing CV disease risk and body weight.

Are low intakes of calcium and potassium important causes of cardiovascular disease?

Inadequate levels of calcium and potassium intake have long been associated with higher blood pressures. Epidemiologic data have suggested these associations and many clinical trials have indicated causal relationships. However, the intervention data are plagued with inconsistent study designs, populations, and results, and there remain many questions regarding dietary recommendations of these nutrients for cardiovascular health. Until recently, nutrition research focused on single-nutrient interventions, generally with disparate results. Recognizing that nutrients are not consumed individually but as combined constituents of a varied diet, efforts in this area have shifted to the role of the overall diet, or dietary patterns, in blood pressure and cardiovascular disease. The suggestions of epidemiologic surveys nearly two decades ago that the total diet has a greater influence on cardiovascular health than do specific components, are now being borne out by randomized controlled trials demonstrating this effect. From these dietary pattern studies, it has become increasingly clear that it is not merely excesses of single nutrients but also deficiencies of multiple nutrients in combination, such as calcium and potassium, that have the greatest dietary effects on cardiovascular health. Several risk factors for cardiovascular disease have now been shown to be reduced with diets that meet the current recommended dietary guidelines, ie, that provide appropriate levels of vitamins, minerals, fiber, and macronutrients. In addition, new data indicate that regular consumption of these diets is associated with decreased mortality. Adequate intake of minerals such as calcium and potassium-specifically derived from foods, where they coexist with other essential nutrients-contributes to cardiovascular as well as overall health.

The power of food to improve multiple cardiovascular risk factors.

Past research efforts to determine the influence of the diet on cardiovascular health have focused on the individual roles of specific dietary components, and have done so with debatable success. Awareness of the impact and complexity of nutrient interactions has expanded in recent years to include assessment of overall dietary patterns as they contribute to lower cardiovascular disease risk. Several large-scale studies have now demonstrated that whereas manipulations of single nutrients may influence some people with selected conditions, it is improving the total dietary profile that will consistently and beneficially effect multiple cardiovascular risk factors including high blood pressure, plasma lipids, hemoglobin A1c, homocysteine, and weight.

Effects of isradipine or enalapril on blood pressure in salt-sensitive hypertensives during low and high dietary salt intake. MIST II Trial Investigators.

This large multicenter study, tested the antihypertensive effects of isradipine, a dihydropyridine calcium channel blocker and enalapril, an angiotensin-converting enzyme inhibitor, in salt-sensitive hypertensive patients under low and high salt intake diets. After a 3-week (weeks -9 to -6) of ad lib salt diet, those patients who had a sitting diastolic blood pressure (SDBP) of > or =95 but < or =115 mm Hg qualified to enter a 3-week (weeks -6 to -3) placebo run-in low salt diet (50 to 80 mmol Na+/day). Then high salt (200 to 250 mmol Na+/day) was added to the placebo treatment for 3 weeks (weeks -3 to 0). Those patients who demonstrated an increase in SDBP > or =5 mm Hg from the low to high salt diet were considered salt sensitive and were randomized into a 4-week (weeks 0 to 4) double-blind treatment period of either isradipine 2.5 to 10 mg twice a day, enalapril 2.5 to 20 mg twice a day, or placebo. Then they entered a 3-week (weeks 4 to 7) placebo washout phase of low salt diet (50 to 80 mmol Na+/day). After week 7 and while the low salt diet was continued the patients were restarted on their double-blind treatment for 4 more weeks (weeks 7 to 11) and the study was completed. Of 1,916 patients screened, 464 were randomized into the double-blind treatment phase and 397 completed the study. Both isradipine and enalapril decreased the sitting systolic blood pressure (SSBP) and SDBP during the high salt diet, to a similar degree, whereas enalapril caused a greater reduction in SSBP and SDBP than isradipine during the low salt diet (11.3 +/- 1.2/7.7 +/- 0.7 mm Hg v 7.7 +/- 0.9/4.8 +/- 0.6 mm Hg, mean +/- SEM, respectively, P < .02). Within drugs, the effect of isradipine on blood pressure (BP) was higher during the high than the low salt diet (14.9 +/- 1.5 v 7.6 +/- 1.3 mm Hg for SSBP and 10.1 +/- 0.6 v 4.8 +/- 0.9 mm Hg for SDBP, P < .001), but enalapril exerted a similar effect during both diets. Because salt restriction lowered both SSBP and SDBP, the lowest BP achieved with both drugs were during the salt restriction phase.

Factors affecting blood pressure responses to diet: the Vanguard study.

To study physiologic factors affecting the blood pressure (BP) response to nonpharmacologic maneuvers, fasting blood glucose, insulin, lipid and mineral levels, urinary mineral excretion, and the calcium regulating hormones parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D (1,25 (OH)2D) were measured in 71 unmedicated hypertensive (26 hypertensive only [HT], 45 hypertensive hyperlipidemic [HTHL]), and 87 normotensive hyperlipidemic (NTHL) control subjects before and during a 10-week multicenter, randomized controlled trial comparing a prepared meal plan (CCNW) with a self-selected diet (SSD) based on nutritionist counseling. Blood pressure fell to a greater extent in hypertensive versus normotensive subjects (-8+/-1/-5+/-1 v -2+/-1/-2+/-1 mm Hg, P < .0001/P < .0001), and on CCNW versus SSD diets (delta systolic BP [SBP]/delta diastolic BP [DBP], P = .033/P = .002). Diet-induced weight change was the strongest correlate of changes in BP (SBP: r = 0.360, P < .0001; DBP: r = 0.414, P < .0001), which, on multivariate analysis for deltaSBP, could partly be accounted for by diet-induced changes in fasting glucose (r = 0.215, P = .009) and cholesterol (r = 0.219, P = .006) levels. Independently of weight, diet-induced changes in SBP also were significantly related to concomitant changes in urinary excretion of potassium (r = -0.285, P = .001), magnesium (r = -0.254, P = .003), and calcium relative to sodium (r = -0.200, P = .021), but not to sodium per se; and to changes in serum potassium (r = -0.249, P = .002), phosphorus (r = -0.279, P = .001), PTH (r = 0.288, P = .0006), and 1,25 D (r = 0.202, P = .017). We conclude that the ability of diet to lower BP successfully may result from the additive contributions of multiple components. Independently of weight loss and the associated changes in circulating glucose and cholesterol, BP is influenced by the increasing provision of minerals such as potassium, magnesium, and calcium, perhaps by virtue of their suppressive effects on circulating vasoactive calcium regulating hormones.

Effects of increased consumption of fluid milk on energy and nutrient intake, body weight, and cardiovascular risk factors in healthy older adults.

OBJECTIVE: To assess the impact of increased consumption of milk, without other dietary advice, on older adults' energy and nutrient intakes, weight, cardiovascular risk factors (blood pressure, plasma lipid levels), and quality of life. SUBJECTS/SETTING: Two hundred four healthy men and women, aged 55 to 85 years, who consumed fewer than 1.5 dairy servings per day were chosen from six US academic health centers. DESIGN: Randomized, controlled open trial. INTERVENTION: Advice to increase skim or 1% milk intake by 3 cups per day (n = 101) or to maintain usual diet (n = 103) for 12 weeks after a 4-week baseline period. MAIN OUTCOME MEASURES: Changes in energy and nutrient intake assessed from 3-day food records, body weight, blood pressure, and plasma lipid levels. STATISTICAL ANALYSES PERFORMED: Group-by-time analysis of variance with repeated-measures, chi 2 test. RESULTS: Compliance with the intervention was good. Compared with controls, participants in the milk-supplemented group significantly increased energy, protein, cholesterol, vitamins A, D, and B-12, riboflavin, pantothenate, calcium, phosphorus, magnesium, zinc, and potassium intakes. Prevalence of nutrient inadequacy, assessed for nutrients with Estimated Average Requirements, decreased among women in the milk group for magnesium (40% at baseline vs 13% at 12 weeks, P < .001) and vitamin B-12 (6% vs 0%, P < .05) and tended to decrease (P < .10) for protein and thiamin (women) and magnesium and vitamin B-6 (men). The milk group gained 0.6 kg more than control group (P < .01); however, weight gain was less than predicted, which suggests some compensation for the added energy from milk. Blood pressure decreased similarly over time in both groups. Total and low-density lipoprotein cholesterol levels, and the ratio of total cholesterol to high-density lipoprotein cholesterol, were unchanged. Triglyceride levels increased within the normal range in the milk group (P = .002). Quality of life scores were high at baseline and remained high throughout. APPLICATIONS/CONCLUSIONS: Older adults can successfully increase milk intake, thereby meaningfully improving their nutrient intakes. Dietitians can play a key role in disseminating this advice.

A randomized trial of improved weight loss with a prepared meal plan in overweight and obese patients: impact on cardiovascular risk reduction.

OBJECTIVE: To assess the long-term effects of a prepackaged, nutritionally complete, prepared meal plan compared with a usual-care diet (UCD) on weight loss and cardiovascular risk factors in overweight and obese persons. DESIGN: In this randomized multicenter study, 302 persons with hypertension and dyslipidemia (n = 183) or with type 2 diabetes mellitus (n = 119) were randomized to the nutrient-fortified prepared meal plan (approximately 22% energy from fat, 58% from carbohydrate, and 20% from protein) or to a macronutrient-equivalent UCD. MAIN OUTCOME MEASURES: The primary outcome measure was weight change. Secondary measures were changes in blood pressure or plasma lipid, lipoprotein, glucose, or glycosylated hemoglobin levels; quality of life; nutrient intake; and dietary compliance. RESULTS: After 1 year, weight change in the hypertension/dyslipidemia group was -5.8+/-6.8 kg with the prepared meal plan vs -1.7+/-6.5 kg with the UCD plan (P<.001); for the type 2 diabetes mellitus group, the change was -3.0+/-5.4 kg with the prepared meal plan vs -1.0+/-3.8 kg with the UCD plan (P<.001) (data given as mean +/- SD). In both groups, both interventions improved blood pressure, total and low-density lipoprotein cholesterol levels, glycosylated hemoglobin level, and quality of life (P<.02); in the diabetic group, the glucose level was reduced (P<.001). Compared with those in the UCD group, participants with hypertension/dyslipidemia in the prepared meal plan group showed greater improvements in total (P<.01) and high-density lipoprotein (P<.03) cholesterol levels, systolic blood pressure (P<.03), and glucose level (P<.03); in participants with type 2 diabetes mellitus, there were greater improvements in glucose (P =.046) and glycosylated hemoglobin (P<.02) levels. The prepared meal plan group also showed greater improvements in quality of life (P<.05) and compliance (P<.001) than the UCD group. CONCLUSIONS: Long-term dietary interventions induced significant weight loss and improved cardiovascular risk in high-risk patients. The prepared meal plan simultaneously provided the simplicity and nutrient composition necessary to maintain long-term compliance and to reduce cardiovascular risk.

The dietary guideline for sodium: should we shake it up? Yes!

The dietary guidelines established under the auspices of public health policy are intended to promote healthy diets in the general public. The current recommendations for sodium intake stem from studies and publications that are older than much of the public they are designed to benefit. The past 2 decades have seen a dramatic increase in our knowledge of nutritional science, particularly our understanding of the role of sodium in blood pressure regulation. With a myriad of data from observational studies and randomized, controlled trials, we have the information to finally put sodium into its correct context in terms of its role in the regulation of blood pressure and hypertension. Not the sole and pervasive dietary villain it was once believed to be, sodium is but one factor in the complex interplay of multiple, inextricably related regulatory systems of which hypertension is the end result. With the data now available concerning dietary sodium, including the minimal and specific blood pressure effects of sodium in normotensive adults and both the benefits and risks of sodium reduction, future public health recommendations can be based on carefully acquired, consistent, and rational science.

Benefits of dairy product consumption on blood pressure in humans: a summary of the biomedical literature.

The inverse relationship between intake of dairy products and blood pressure levels was first suggested by several epidemiologic surveys in the early 1980's that revealed low calcium intake in populations with increased prevalence of hypertension. Subsequent laboratory and clinical investigations provided further evidence of the association between calcium and blood pressure, but the results of these studies were often inconsistent due to variations in study design and methods, study participants and calcium sources. The recently published results of the large and carefully executed Dietary Approaches to Stop Hypertension Study, "DASH," which demonstrated a dramatic blood-pressure lowering effect of diets rich in dairy products, fruits and vegetables, addressed many of the issues contributing to the inconsistencies in the blood pressure-calcium data. In the following review, we discuss the evolution of the scientific evidence of the association between dietary calcium intake and blood pressure, the findings and significance of the DASH trial and the consensus that now exists among health professionals regarding the importance of adequate dairy product intake for optimal blood pressure regulation.

Finding consensus in the dietary calcium-blood pressure debate.

No single study or avenue of investigation can resolve the scientific controversies that entangle efforts to determine the effects of specific nutrients on medical conditions. To reach consensus in this area requires a substantial body of plausible, reproducible and consistent data from various investigative approaches--such as the data that now exist regarding the relationship between dietary calcium and blood pressure. In this paper we describe the plethora of epidemiological and clinical studies and analyses that have been published in the last two years and which cumulatively reveal the consistency of the available data regarding the influence of dietary calcium on blood pressure regulation. Nearly 20 years of investigation in this area has culminated in remarkable and compelling agreement in the data, confirming the need for and benefit of regular consumption of the recommended daily levels of dietary calcium.

Dietary changes favorably affect bone remodeling in older adults.

OBJECTIVE: To determine whether dietary counseling to increase milk intake could produce useful changes in the calcium economy and what, if any, other nutrition-related changes might be produced. DESIGN: Randomized, open trial. SUBJECTS/SETTING: Two hundred four healthy men and women, aged 55 to 85 years, who habitually consumed fewer than 1.5 servings of dairy foods per day. Six academic health centers in the United States. INTERVENTION: Subjects were instructed to consume 3 servings per day of nonfat milk or 1% milk as a part of their daily diets, or to maintain their usual diets, for a 12-week intervention period, which followed 4 weeks of baseline observations. MAIN OUTCOME MEASURES: Energy and nutrient intake assessed from milk intake logs and 3-day food records; serum calciotrophic hormone levels at baseline and at 8 and 12 weeks; urinary excretion of calcium and N-telopeptide at 12 weeks. STATISTICAL ANALYSES: Repeated-measures analysis of variance. RESULTS: In the milk-supplemented group, calcium intake increased by 729 +/- 45 mg/day (mean +/- standard error), serum parathyroid hormone level decreased by approximately 9%, and urinary excretion of N-telopeptide, a bone resorption marker, decreased by 13%. Urine calcium excretion increased in milk-supplemented subjects by 21 +/- 7.6 mg/day (mean +/- standard error), less than half the amount predicted to be absorbed from the increment in calcium intake. All of these changes were significantly different from baseline values in the milk group and from the corresponding changes in the control group. Bone-specific alkaline phosphatase level (a bone formation marker) fell by approximately 9% in both groups. Serum level of insulin-like growth factor-1 (IGF-1) rose by 10% in the milk group (P < .001), and the level of insulin-like growth factor binding protein-4 (IGFBP-4) fell slightly (1.9%) in the milk group and rose significantly (7.9%) in the control group (P < .05). APPLICATIONS/CONCLUSIONS: The changes observed in the calcium economy through consumption of food sources of calcium are similar in kind and extent to those reported previously for calcium supplement tablets. The increase in IGF-1 level and the decrease in IBFBP-4 level are new observations that are beneficial for bone health. Important improvements in skeletal metabolism can feasibly occur in older adults by consumption of food sources of calcium. Dietitians can be confident that food works, and that desired calcium intakes can be achieved using food sources.

Increased dietary micronutrients decrease serum homocysteine concentrations in patients at high risk of cardiovascular disease.

BACKGROUND: Elevated blood homocysteine is a risk factor for cardiovascular disease. A 5-micromol/L increase is associated with an approximately 70% increase in relative risk of cardiovascular disease in adults. For patients with established risk factors, this risk is likely even greater. OBJECTIVE: Effects of increased dietary folate and recommended intakes of vitamins B-12 and B-6 on serum total homocysteine (tHcy) were assessed in individuals at high risk of cardiovascular disease. DESIGN: This trial was conducted at 10 medical research centers in the United States and Canada and included 491 adults with hypertension, dyslipidemia, type 2 diabetes, or a combination thereof. Participants were randomly assigned to follow a prepared meal plan (PMP; n = 244) or a self-selected diet (SSD; n = 247) for 10 wk, which were matched for macronutrient content. The PMP was fortified to provide >/=100% of the recommended dietary allowances for 23 micronutrients, including folate. RESULTS: Mean folate intakes at 10 wk were 601 +/- 143 microgram/d with the PMP and 270 +/- 107 microgram/d with the SSD. With the PMP, serum tHcy concentrations fell from 10.8 +/- 5.8 to 9.3 +/- 4.9 micromol/L (P < 0.0001) between weeks 0 and 10 and the change was associated with increased intakes of folate, vitamin B-12, and vitamin B-6 and with increased serum and red blood cell folate and serum vitamin B-12 concentrations. tHcy concentrations did not change significantly with the SSD. CONCLUSIONS: The PMP resulted in increased intakes and serum concentrations of folate and vitamin B-12. These changes were associated with reduced serum tHcy concentrations in persons at high risk of cardiovascular disease.

Nutritionally complete prepared meal plan to reduce cardiovascular risk factors: a randomized clinical trial.

OBJECTIVE: To compare a nutritionally complete prepared meal plan that meets national dietary guidelines to usual-care dietary therapy for hypertension, dyslipidemia, and glycemic control. DESIGN: Randomized, controlled trial. SUBJECTS/SETTING: Outpatients with hypertension, dyslipidemia, or diabetes mellitus (n = 251) were recruited at 6 medical centers in the United States and Canada. INTERVENTION: The prepared meal plan, which was developed by university-based nutrition and cardiovascular scientists and food technologists at Campbell's Center for Nutrition & Wellness (CCNW), provided the optimal levels of macronutrients and micronutrients recommended for cardiovascular risk reduction in a variety of prepackaged meals and snacks. After a 4-week pretrial period to assess baseline state, participants were randomized to the CCNW plan or "usual-care" diet for 10 weeks. MAIN OUTCOME MEASURES: Blood pressure, carbohydrate metabolism, lipoproteins, homocysteine, weight, nutrient intake, compliance. STATISTICAL ANALYSES PERFORMED: Repeated measures analysis of variance. RESULTS: Lipoproteins, carbohydrate metabolism, blood pressure, and weight improved on both plans. Mean differences (+/- standard deviation) between baseline and follow-up for the CCNW plan and the usual-care plan, respectively, were total cholesterol, -0.41 +/- 0.64 and -0.20 +/- 0.50 mmol/L (between-group P < .01); plasma glucose, -0.7 +/- 1.7 and -0.3 +/- 1.3 mmol/L (P < .05); systolic blood pressure, -5.2 +/- 10.0 and -4.7 +/- 9.0 mm Hg (P = .67), diastolic blood pressure, -3.8 +/- 5.9 and -2.2 +/- 5.5 mm Hg (P < .05); and homocysteine, -1.3 +/- 3.8 and 0.2 +/- 3.4 mumol/L (P < .01). The CCNW plan led to greater weight loss than the usual-care diet (-5.5 +/- 3.8 kg vs -3.0 +/- 3.2 kg, P < .0001). APPLICATIONS/CONCLUSION: The nutritionally complete CCNW plan offers greater improvements in lipids, blood sugars, homocysteine, and weight loss than usual-care diet therapy. This prepackaged comprehensive nutrition program can augment both the prescription and practice of optimal dietary therapy.

Nonpharmacologic therapy in hypertension: from single components to overall dietary management.

Improved lifestyle and dietary practices are now recognized as essential factors in the optimal management of high blood pressure. This chapter discusses the nonpharmacologic approaches that are generally recommended for hypertension treatment as well as prevention, including summaries of the evidence on which these recommendations are based. For many of these approaches, specifically dietary modifications, the evidence is strong but not yet definitive. Potential sources of the conflicting data and the lack of scientific consensus are addressed, as well as recent findings of the effects of the total diet and dietary patterns that may ultimately resolve much of the controversy regarding nonpharmacologic means of treating and preventing hypertension.

Multicenter randomized trial of a comprehensive prepared meal program in type 2 diabetes.

OBJECTIVE: To evaluate the clinical effects of a comprehensive prepackaged meal plan, incorporating the overall dietary guidelines of the American Diabetes Association and other national health organizations, relative to those of a self-selected diet based on exchange lists in free-living individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 202 women and men (BMI < or = 42 kg/m2) whose diabetes was treated with diet alone or an oral hypoglycemic agent were enrolled at 10 medical centers. After a 4-week baseline period, participants were randomized to a nutrient-fortified prepared meal plan or a self-selected exchange-list diet for 10 weeks. On a caloric basis, both interventions were designed to provide 55-60% carbohydrate, 20-30% fat, and 15-20% protein. At intervals, 3-day food records were completed, and body weight, glycemic control, plasma lipids, and blood pressure were assessed. RESULTS: Food records showed that multiple nutritional improvements were achieved with both diet plans. There were significant overall reductions in body weight and BMI, fasting plasma glucose and serum insulin, fructosamine, HbA1c, total and LDL cholesterol, and blood pressure (P < 0.001 or better for all). In general, differences in major end points between the diet plans were not statistically significant. CONCLUSIONS: Glycemic control and cardiovascular risk factors improve in individuals with type 2 diabetes who consume diets in accordance with the American Diabetes Association guidelines. The prepared meal program was as clinically effective as the exchange-list diet. The prepared meal plan has the additional advantages of being easily prescribed and eliminating the complexities of meeting the multiple dietary recommendations for type 2 diabetes management.

Farnesol blocks the L-type Ca2+ channel by targeting the alpha 1C subunit.

We recently demonstrated that farnesol, a 15-carbon isoprenoid, blocks L-type Ca2+ channels in vascular smooth muscle cells. To elucidate farnesol's mechanism of action, we performed whole-cell and perforated-patch clamp experiments in rat aortic A7r5 cells and in Chinese hamster ovary (CHO) C9 cells expressing smooth muscle Ca2+ channel alpha 1C subunits. Farnesol dose-dependently and voltage-independently inhibited Ba2+ currents in both A7r5 and CHOC9 cells, with similar half-maximal inhibitions at 2.6 and 4.3 micromol/L, [corrected] respectively (P=NS). In both cell lines, current inhibition by farnesol was prominent over the whole voltage range without changes in the current-voltage relationship peaks. Neither intracellular infusion of the stable GDP analogue guanosine-5'-O-(2-thiodiphosphate) (100 micromol/L) [corrected] via the patch pipette nor strong conditioning membrane depolarization prevented the inhibitory effect of farnesol, which indicates G protein-independent inhibition of Ca2+ channels. In an analysis of the steady-state inactivation curve for voltage dependence, farnesol induced a significant, negative shift ( approximately 10 mV) of the potential causing 50% channel inactivation in both cell lines (P<0. 001). In contrast, the steepness factor characterizing the voltage sensitivity of the channels was unaffected. Unlike pharmacological Ca2+ channel blockers, farnesol blocked Ca2+ currents in the resting state: initial block was 63+/-8% in A7r5 cells and 50+/-9% in CHOC9 cells at a holding potential of -80 mV. We then gave 500 mg/kg body weight farnesol by gavage to Sabra hypertensive and normotensive rats and found that farnesol reduced blood pressure significantly in the hypertensive strain for at least 48 hours. We conclude that farnesol may represent an endogenous smooth muscle L-type Ca2+ channel antagonist. Because farnesol is active in cells expressing only the pore-forming alpha1 subunit, the data further suggest that this subunit represents the molecular target for farnesol binding and principal action. Finally, farnesol has a blood pressure-lowering action that may be relevant in vivo.

Effects of FK506 in rat and human resistance arteries.

BACKGROUND: FK506 is widely used in organ transplantation and causes hypertension. However, little is known about the impact of the drug on the cardiovascular system. METHODS: We therefore investigated the effect of FK506 on resistance artery and blood pressure responsiveness to vasoconstrictors and vasodilators. Studies were conducted in vitro using human and murine resistance artery, ex vivo in resistance artery isolated from rats treated with FK506 (6 mg/kg/day), and in vivo in conscious, treated animals. RESULTS: In vitro exposure (24 hr) of human and rat resistance artery to FK506 (1000 ng/ml) increased the sensitivity to norepinephrine (NE) and impaired the response to acetylcholine (Ach) and sodium nitroprusside (SNp). In contrast, arteries isolated from rats given FK506 for eight days showed a reduced sensitivity to NE (P < 0.05) and a normal endothelium-dependent relaxation. Their incubation with L-arginine caused a significant reduction in Ach sensitivity in the FK506 group (P < 0.05) but not in controls, suggesting enhancement of nitric oxide production by the drug. The sensitivity to SNp was reduced, as in the in vitro experiments (P < 0.05). Rats given FK506 for eight days presented blood pressure similar to that in controls but also presented signs of a compensatory response to excess vasodilation: tachycardia (P < 0.01), reduced blood pressure sensitivity to NE and Ach, blunted heart rate response to both agonists, and exaggerated hypotension at high doses of Ach. After 21 days of treatment, blood pressure remained similar to that in controls, but resistance artery showed further functional deterioration, with significant impairment of the maximum responses to Ach and to SNp. CONCLUSION: FK506 presents significant vascular toxicity affecting mainly smooth muscle relaxation and alters vascular hemodynamics. The data suggest that similar cardiovascular changes may occur in transplant patients and represent the forerunner of hypertension often seen with more prolonged use of the drug.