Julie Gardener
New Member
Endocannabinoids, Blood Pressure and the Human Heart
R. SarzaniArticle first published online: 17 APR 2008
DOI: 10.1111/j.1365-2826.2008.01677.x
Abstract
The effects of exogenous and endogenous cannabinoids on the cardiovascular system have been the focus of extensive research. The direct and indirect effects of cannabinoids on heart and blood vessels depend upon experimental conditions, animal species, and, in humans, clinical background. Cannabinoids decrease blood pressure in hypertensive rodents primarily because of decrease cardiac contractility, leading researchers to postulate a role in the treatment of hypertension and cardiac hypertrophy. Rimonabant, the CB1 receptor blocker in clinical use in many countries, induced a marked and sustained increase in cardiac contractility and blood pressure in hypertensive rats but, on the contrary, contributed to decrease blood pressure in weight-loss clinical trials especially in obese patients with hypertension.
In the midst of the obesity pandemic and from the cardiometabolic point of view, the overactivation of the endocannabinoid system present in intra-abdominal obesity appears to be very harmful. Moreover, novel human findings suggest a relationship between CB1-mediated overactive endocannabinoid system and nephrovascular damage. Overall, it appears that CB1 blockade in obese patients behaves as a 'multiplier' of the many beneficial effects of body weight loss induced by a hypocaloric diet and increased physical activity (the 'lifestyle changes' that are so difficult to start and maintain). Thus, the concept − based mostly on experimental results using in vitro or animal models − that CB1-mediated endocannabinoid effects are beneficial for the cardiovascular system should be revised at least in obese patients.
The results of long-term clinical trials such as the STRADIVARIUS and the CRESCENDO trials will tell whether the improvement in the cardiometabolic risk profile induced by Rimonabant translates into vascular changes, reducing the risk of myocardial infarction, stroke and cardiovascular death in patients with abdominal obesity. Time (and much more work) will tell us much more about cannabinoids and the human heart.
The effects of exogenous and endogenous cannabinoids on the cardiovascular system have been the focus of extensive research, particularly in the past 5 years. Disappointingly, there is currently only one certainty about cannabinoids and the cardiovascular system: the direct and indirect effects of cannabinoids on heart and blood vessels depend upon experimental conditions, animal species, and, in humans, clinical background. Many discrepancies have been found in vitro versus in vivo studies and in anaesthetised versus conscious animals: these results have been recently summarised in comprehensive reviews focusing on these aspects (1, 2). Therefore, the focus of this review, enriched with some novel (although preliminary) data from clinical studies, will be endocannabinoids and the human cardiovascular system, and in vitro or animal data will be taken into consideration only where necessary.
Smoking is certainly deleterious to the cardiovascular system. Nevertheless, chronic smoking of cannabis has been associated with lower blood pressure and with symptomatic hypotension that was reversed by elevated dosages of rimonabant (3), the receptor blocker now in clinical use in Europe and a number of other countries. In addition to the negative effect of smoking itself, the conflicting effects of marijuana smoke on atherosclerotic heart disease might depend on the simultaneous activation of cannabinoid receptors CB1 and CB2 by Δ9--tetrahydrocannabinol (Δ9-THC), the major active component of marijuana. Indeed, low doses of Δ9-THC inhibited the progression of established atherosclerotic lesions in a murine model of atherosclerosis (4). Moreover, the function of atherosclerotic plaque-resident and incoming immune cells can be favourably modulated by the activation of CB2 receptors. In humans, however, the simultaneous Δ9-THC activation of CB1 receptors in the brain can induce, at least in some conditions, a cardiovascular stress response with increased cardiac oxygen consumption and reduced coronary blood flow (5).
We are currently in the midst of an obesity pandemic. Increased visceral adiposity even in overweight (BMI ≥ 25 and < 30 kg/m2) subjects is associated with increased metabolic risk (diabetes and atherogenic dyslipidaemia) and cardiovascular risk (myocardial infarction, ictus and death). This increased cardiometabolic risk in viscerally obese subjects might, at least in part, depend on overactivation of the endogenous cannabinoid system (ECS), as described below. Therefore, special emphasis will be placed here on the available data on endocannabinoids and the cardiovascular system in obese patients.
Endocannabinoids, heart, blood vessels and blood pressure: evidence in humans
Administration of cannabinoids in volunteers caused CB1-mediated pronounced tachycardia (compared with bradycardia in animals) that was apparently caused by increased circulating noradrenaline (6, 7). Thus the inhibition of the sympathetic nervous system (SNS) observed in animal models appear to be absent in non-anaesthetised humans, and the contrasting documented stimulation of SNS is difficult to explain. We speculate that perhaps it is owing to lower cannabinoid doses used in conscious volunteers?
It is unclear to what extent other receptors, including the vanilloid type 1 receptor, are involved in the resulting overall cannabinoid cardiovascular effects in animals and humans (1, 2). There is evidence that a non-CB1/CB2 and non-vanilloid receptor induces inotropic and coronary vasodilatatory response that can be blocked by rimonabant (8). Despite expectations, the novel endocannabinoid receptor GPR55, activated by atypical cannabinoids, does not mediate the vasodilator effect (9). Receptors aside, it is interesting that an overproduction of endocannabinoids has been reported in conditions associated with severe hypotension, such as cardiogenic shock or decompensated cirrhosis, where monocytes isolated from the blood of cirrhotic patients were found to contain elevated levels of N-arachidonoylethanolamine (anandamide), and caused CB1-receptor-mediated hypotension when injected into rats (10).
The CB1 receptor appears to mediate a direct negative inotrope effect of cannabinoids on human myocardium: anandamide in vitro induced a negative inotropic effect in isolated human atrial heart muscle (11). There is also evidence for the existence of a CB1-receptor-mediated tonic inhibition of the beta-adrenergic responsiveness of isolated cardiac ventricular muscle in a rat model of biliary cirrhosis (12), where increased local endocannabinoid synthesis could play an important role in the blunted contractile responsiveness of cirrhotic cardiomyopathy. By contrast, anandamide does not induce vasorelaxation in porcine coronary vessels (13) or in human myometrial arteries (14).
In addition to the complexities and discrepancies described above, as well as the wide gaps in our knowledge of cannabinoid effects on the human cardiovascular system, at least three other aspects need to be considered: (i) there are many different endocannabinoids and many more cannabinoid-like substances; (ii) at least three multiple splice CB1 receptor variants exist in humans (15); and (iii) CB1 receptors can heterodimerise and this can change the function and overall final effects of cannabinoids (16). Thus, understanding the ECS is not an easy task especially when human beings are considered. Nevertheless, the results of the Rimonabant in Obesity (RIO) trials described below reported a significant decrease in blood pressure especially in hypertensive obese patients, indicating that the blockade of an overactive ECS in human obesity has beneficial cardiovascular effects despite experimental evidence from animal models.
Endocannabinoids and the cardiovascular system in human obesity
Human obesity is strongly associated with increased blood pressure, increased left ventricular mass, and increased cardiovascular events. Moreover, body weight changes are accompanied by blood pressure changes in the same direction (17).
Because the effects of cannabinoids on the cardiovascular system are dependent on the underlying conditions, in obesity, especially when visceral obesity is present, the cardiovascular effects of cannabinoids can be different from what observed in most experimental conditions tested to date. First, the available evidence indicates that an overactivation of the ECS is present in human obesity (18). Surprisingly, and in contrast with the current view of endocannabinoids as 'on demand', locally active, and short-lived substances, increased 2-arachidonoylglycerol (2AG) levels were found in plasma of obese women (18). Such increased circulating cannabinoids were in strong correlation with visceral, intra-abdominal adiposity (19, 20) and related to cardiometabolic risk factors in obese men (20). Indeed, increased production of 2AG has been found particularly in visceral adipose tissue of obese patients (21). This contradiction to the classic view of the ECS, makes understanding the pathophysiological implications appears difficult. The increased synthesis of endocannabinoids is so relevant it can be measured as systemic 'spillover' in the venous blood drawn from an upper limb of obese subjects. We have now more questions than answers. What is the meaning of increased circulating cannabinoids? Is it really just the result of spillover from tissues? What main cell type produces them? Are they carried over by lipoproteins and/or albumin and thus reflect their levels? And, primarily, how much do they affect metabolism, heart, and cardiovascular system?
The prevalent view, based mostly on mouse and rat models, is still that the endocannabinoid system plays an important role in the cardiovascular system, particularly in hypertension (1). The decrease in blood pressure induced by both Δ9-THC (22) and anandamide (23, 24) was larger and lasted longer in spontaneously hypertensive rats (SHRs) than in normotensive rats. These effects were primarily owing to decrease cardiac contractility and not to a reduction in peripheral resistance. When rimonabant was given to anaesthetised SHRs, there was a marked and sustained increase in cardiac contractility and blood pressure (24). These findings lead to the suggestion that inhibitors of fatty acid amide hydrolase (FAAH) could play a role in the treatment of hypertension and cardiac hypertrophy (1), despite the fact that in vivo FAAH does not seem to degrade 2AG (1).
Unfortunately for our understanding but luckily for our patients, CB1-receptor blockade using rimonabant was associated with a reduction in blood pressure comparable to that expected through weight loss in the RIO trials. The blood pressure reduction was especially important in obese hypertensive patients (see below). It is possible that in conditions such as obesity-associated hypertension, endocannabinoids, although increased, have lost their blood pressure lowering effect that is present in younger, healthier subjects. Thus, increased age and adiposity might be other key factors influencing the circulatory response to endocannabinoids. Unfortunately human data are lacking and even animal data have been obtained using mostly young, male, non-obese and non-hypertensive rodents. Further research on this is certainly needed.
The endocannabinoid system and the human cardiovascular system: novel experimental evidence
Increased visceral adiposity is regarded as the 'link' between overweight and cardiometabolic complications. A dysregulated, overstimulated ECS in visceral adipose tissue appears to significantly contribute to the cardiometabolic complications of visceral obesity (18—21). On this trail, we have recently obtained novel data supporting a relationship between the ECS and the human cardiovascular system. In an ongoing study on a large number of patients uninephrectomised for localised intracapsular carcinoma, renal samples from the spared portion of the kidney, as well as visceral and subcutaneous adipose tissue, were studied. Taking into consideration all the relevant anthropometric, metabolic and cardiovascular parameters of this non-diabetic population, we found that in patients with more advanced arteriolar damage (Fig. 1) − damage usually resulting from ageing and hypertension− CB1 receptor gene expression was significantly increased in visceral perirenal adipose tissue (Fig. 2), even after correction for other variables such as blood pressure. These findings (Sarzani R., Bordicchia M, Marcucci P, Minardi D, Muzzonigro G, Mazzucchelli R, Montironi R, manuscript in preparation) suggest that an overactive ECS in visceral adipose tissue is related to vascular damage. Although an increase in circulating endocannabinoids has been documented (18—20), the most likely link between CB1 overexpression in visceral adipose tissue and vascular damage is adiponectin, which is reduced in obesity but increases after CB1 blockade (25). Rimonabant is also able to increase HDL cholesterol and reduce small, dense, oxidation-prone LDL (25), key mediators of vascular damage in large and small arteries. Nevertheless, despite decades of good research, our comprehension of the relationship between hypertension, lipid dysmetabolism and cardiovascular damage is far from clear. To the best of our knowledge, the first reported hypertension-related change in vascular gene expression was dramatic downregulation of an intracellular fatty acid binding protein (FABP), largely expressed in aortic adventitial preadipocyte/adipocytes (26). The importance of the downregulation of FABP in hypertension remains unclear, but it is likely to reduce peripheral non-esterified fatty acids (NEFA) uptake and contribute to the rise in circulating NEFA levels that is often documented in hypertension, especially when associated with insulin resistance. Some NEFAs are also endocannabinoids precursors and this appears to be a promising novel pathway to explore to understand the link between ECS and human hypertension.
Figure 1. Different degree of renal arteriolar damage in two different patients. (a) Intimal hyperplasia. (b) Severe hyperplasia and fibrosis. Scale, 200 ×.
Figure 2. CB1 receptor gene expression in visceral adipose tissue (VAT) in patients with different severity of arteriolar microvascular damage. Significantly higher CB1 gene expression was present in VAT of the patients with a more severe degree of renal microvascular damage.
The RIO trials
The best evidence to date on the cannabinoid system and the cardiovascular system in humans has come from the RIO trials; RIO-Lipids (25), RIO-Europe (27), RIO-North America (28) and RIO-Diabetes (29). In these trials, obese patients were treated with the rimonabant, which, at 20 mg (od) enhanced the loss of body weight more than lifestyle measures and with an improvement in metabolic parameter that exceeded that expected from weight loss by about 50% (25).
In the large number of obese patients studied, 20 mg rimonabant not only did not increased blood pressure (as expected from most animal studies) but blood pressure was reduced, reaching significance in RIO Lipids, RIO Diabetes, and in all RIO studies after meta-analysis (25, 29—31). Blood pressure reduction was seen in RIO Diabetes, despite the overall lower loss in body weight compared with the previous other three trials cited above (25, 27—29). More interestingly, considering only patients with high blood pressure at baseline (defined as ≥ 140/90 mmHg for RIO Lipids, RIO North America and RIO Europe; ≥ 130/85 mmHg for RIO Diabetes), the placebo-subtracted significant reduction in systolic and diastolic blood pressure was −2.5 and 2 mmHg, respectively (30, 31). These reduction are apparently small, but a fall of 2 mmHg systolic blood pressure translates to a 10% reduction in stroke mortality and 7% reduction in mortality for ischaemic heart disease (32). Although the RIO trials were not designed to study blood pressure variations, these findings are not only reassuring but also important for the overall cardiovascular benefits from CB1 blockade. Indeed, together with the positive metabolic/dyslipidaemic results, it is clear that blocking cannabinoid effects mediated by the CB1 receptor will result in an important reduction in cardiovascular risk in obese patients. Overall, it appears that Rimonabant behaves as a 'multiplier' of the many beneficial effects of body weight loss induced by a hypocaloric diet and increased physical activity.
Thus, the concept, based mostly on experimental results with in vitro or animal models, that CB1-mediated endocannabinoids effects are beneficial to the cardiovascular system should be revised, at least in obese patients.
Conclusions
We are still very far from understanding the endocannabinoids system in humans, particularly with regard to the short- and long-term effects on the cardiovascular system. Thus, some answers will come from the publication of the results of longer-term clinical trials such as the STRADIVARIUS (Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant — the Intravascular Ultrasound Study; ClinicalTrials.gov Identifier: NCT00124332) trial, due for completion in August 2007, which tests whether the improvement in the cardiometabolic risk profile induced by rimonabant translates into changes within the coronary circulation. The enrolled patients with abdominal obesity, with metabolic syndrome and/or smokers, have a documented 20—50% stenosis by coronary angiography. The volume of atheroma has also been assessed by intravascular ultrasound and by repeating coronary angiogram. The CRESCENDO trial (Comprehensive Rimonabant Evaluation Study of Cardiovascular ENDpoints and Outcomes; ClinicalTrials.gov Identifier: NCT00263042), which is still recruiting subjects and is ongoing, will help clarify the cardiovascular effects of long-term CB1 blockade, because it will assess whether rimonabant reduces the risk of myocardial infarction, stroke and cardiovascular death in patients with abdominal obesity and with one coronary heart disease equivalent or two major risk factors for cardiovascular disease. Time (and much more work) will tell us much more about cannabinoids and the human heart.
Acknowledgements
I thank all the staff in my lab, and in particular Dr Marica Bordicchia and Dr Pierfrancesco Marcucci, for ongoing research on the endocannabinoid system in humans. I wish also to thank Dr Muzzonigro, Dr Minardi, Dr Montironi, and Dr Mazzucchelli, all from the University of Ancona-Politecnica delle Marche, Ancona, Italy, for their ongoing collaborative effort.
Conflicts of interest
The author has declared no conflicts of interest.
References
1
Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006; 58: 389—462.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 293
2
Mendizábal VE, Adler-Graschinsky E. Cannabinoids as therapeutic agents in cardiovascular disease: a tale of passions and illusions. Br J Pharmacol 2007; 151: 427—440.
Direct Link:
AbstractFull Article (HTML)PDF(171K)References
3
Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, Huestis MA. The cannabinoid CB1 receptor antagonist rimonabant attenuates the hypotensive effect of smoked marijuana in male smokers. Am Heart J 2006; 151: 754.e1—754.e5.
CrossRef,PubMed,ChemPort,Web of Science®
4
Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard JL, Mach F. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 2005; 434: 782—786.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 127,ADS
5
Roth M. Pharmacology: marijuana and your heart. Nature 2005; 434: 708—709.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 7,ADS
6
Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, Frank RA. Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry 2001; 58: 322—328.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 136
7
Jones RT. Cardiovascular system effects of marijuana. J Clin Pharmacol 2002; 42: 58S—63S.
PubMed,ChemPort,Web of Science® Times Cited: 49
8
Ford WR, Honan S, White R, Hiley R. Evidence of a novel site mediating anandamide-induced negative inotropic and coronary vasodilatator responses in rat isolated hearts. Br J Pharmacol 2002; 135: 1191—1198.
Direct Link:
AbstractFull Article (HTML)PDF(202K)References
9
Johns DG, Behm DJ, Walker DJ, Ao Z, Shapland EM, Daniels DA, Riddick M, Dowell S, Staton PC, Green P, Shabon U, Bao W, Aiyar N, Yue TL, Brown AJ, Morrison AD, Douglas SA. The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects. Br J Pharmacol 2007; 152: 825—831.
Direct Link:
AbstractFull Article (HTML)PDF(154K)References
10
Bátkai S, Jarai Z, Wagner JA, Goparaju SK, Varga K, Liu J, Wang L, Mirshahi F, Khanolkar AD, Makriyannis A, Urbaschek R, Garcia N Jr, Sanyal AJ, Kunos G. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 2001; 7: 827—832.
CrossRef,PubMed
11
Bonz A, Laser M, Kullmer S, Kniesch S, Babin-Ebell J, Popp V, Ertl G, Wagner JA. Cannabinoid acting on CB1 receptors decrease contractile performance in human atrial muscle. J Cardiovasc Pharmacol 2003; 41: 657—664.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 53
12
Gaskari SA, Liu H, Moezi L, Li Y, Baik SK, Lee SS. Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct-ligated rats. Br J Pharmacol 2005; 146: 315—323.
Direct Link:
AbstractFull Article (HTML)PDF(224K)References
13
Fleming I, Schermer B, Popp R, Busse R. Inhibition of the production of endothelium-derived hyperpolarizing factor by cannabinoid receptor agonists. Br J Pharmacol 1999; 126: 949—960.
Direct Link:
AbstractFull Article (HTML)PDF(365K)References
14
Kenny LC, Baker PN, Kendall DA, Randall MD, Dunn WR. The role of gap junctions in mediating endothelium-dependent responses to bradykinin in myometrial small arteries isolated from pregnant women. Br J Pharmacol 2002; 136: 1085—1088.
Direct Link:
AbstractFull Article (HTML)PDF(130K)References
15
Ryberg E, Vu HK, Larsson N, Groblewski T, Hjorth S, Elebring T, Sjogren S, Greasley PJ. Identification and characterisation of a novel splice variant of the human CB1 receptor. FEBS Lett 2005; 579: 259—264.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 34
16
Ellis J, Pediani JD, Canals M, Milasta S, Milligan G. Orexin-1 receptor-cannabinoid CB1 receptor heterodimerization results in both ligand-dependent and -independent coordinated alterations of receptor localization and function. J Biol Chem 2006; 281: 38812—38824.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 43
17
Neter J, Stam B, Kok F. Influences of weight reduction on blood pressure a meta-analysis of randomized controlled trials. Hypertension 2003; 42: 878—884.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 132
18
Engeli S, Bohnke J, Feldpausch M, Gorzelniak K, Janke J, Batkai S, Pacher P, Harvey-White J, Luft FC, Sharma AM, Jordan J. Activation of the peripheral endocannabinoid system in human obesity. Diabetes 2005; 54: 2838—2843.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 173
19
Bluher M, Engeli S, Kloting N, Berndt J, Fasshauer M, Bátkai S, Pacher P, Schon MR, Jordan J, Stumvoll M. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 2006; 55: 3053—3060.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 110
20
Côté M, Matias I, Lemieux I, Petrosino S, Alméras N, Després JP, Di Marzo V. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes 2007; 31: 692—699.
PubMed
21
Matias I, Gonthier MP, Orlando P, Martiadis V, De Petrocellis L, Cervino C, Petrosino S, Hoareau L, Festy F, Pasquali R, Roche R, Maj M, Pagotto U, Monteleone P, Di Marzo V. Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab 2006; 91: 3171—3180.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 151
22
Kosersky DS. Antihypertensive effects of delta9-tetrahydrocannabinol. Arch Int Pharmacodyn Ther 1978; 233: 76—81.
PubMed,ChemPort,Web of Science® Times Cited: 9
23
Lake KD, Martin BR, Kunos G, Varga K. Cardiovascular effects of anandamide in anesthetized and conscious normotensive and hypertensive rats. Hypertension 1997; 29: 1204—1210.
PubMed,ChemPort,Web of Science® Times Cited: 86
24
Bátkai S, Pacher P, Kunos G. Endocannabinoid acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation 2004; 110: 1996—2002.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 105
25
Desprès J.P, Golay A, Sjosrom L, for the RIO-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005; 353: 2121—2134.
CrossRef,PubMed,Web of Science® Times Cited: 580
26
Sarzani R, Claffey KP, Chobanian AV, Brecher P. Hypertension induces tissue-specific gene suppression of a fatty acid binding protein in rat aorta. Proc Natl Acad Sci U S A 1988; 85: 7777—7781.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 28,ADS
27
Van Gaal L, Rissanen A, Scheen A, Ziegler O, Rossner S, for the RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from RIO-Europe study. Lancet 2005; 365: 1389—1397.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 592
28
Pi-Sunyer XF, Aronne LJ, Heshmati HM, Devin J, Rosenstock J, RIO-North America study Group. Effect of rimonabant, a cannabinoi-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients. JAMA 2006; 295: 761—775.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 444
29
Scheen A.J, Finer P, Hollander P, Jensen MD, Van Gaal LF, RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006; 368: 1660—1672.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 270
30
Rucker D, Padwal R, Li SK, Curioni C, Lau DC. Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 2007; 335: 1194—1199.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 113
31
Ruilope LM, Després JP, Scheen A, Pi-Sunyer X, Mancia G, Zanchetti A, Van Gaal L. Effect of rimonabant on blood pressure in overweight/obese patients with/without co-morbidities: analysis of pooled RIO study results. J Hypertens 2008; 26: 357—367.
CrossRef,PubMed,ChemPort,Web of Science® Times Cited: 27
32
Lewington S, Clarke R, Quizilbash N, Peto R, Collins R. Age-Specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903—1913.
CrossRef,PubMed,Web of Science® Times Cited: 1390
Source: Endocannabinoids, Blood Pressure and the Human Heart - Sarzani - 2008 - Journal of Neuroendocrinology - Wiley Online Library
