Marja-Leena Nurminen

Coffee, caffeine and blood pressure: a critical review

Objective: We review the published data relating to intake of coffee and caffeine on blood pressure in man. We also refer to studies on the possible mechanisms of actions of these effects of caffeine.Design: The MEDLINE and Current Contents databases were searched from 1966 to April 1999 using the text words ‘coffee or caffeine’ and ‘blood pressure or hypertension’. Controlled clinical and epidemiologic studies on the blood pressure effects of coffee or caffeine are reviewed. We also refer to studies on the possible mechanisms of action of these effects of caffeine.Results: Acute intake of coffee and caffeine increases blood pressure. Caffeine is probably the main active component in coffee. The pressor response is strongest in hypertensive subjects. Some studies with repeated administration of caffeine showed a persistent pressor effect, whereas in others chronic caffeine ingestion did not increase blood pressure. Epidemiologic studies have produced contradictory findings regarding the association between blood pressure and coffee consumption. During regular use tolerance to the cardiovascular responses develops in some people, and therefore no systematic elevation of blood pressure in long-term and in population studies can be shown.Conclusions: We conclude that regular coffee may be harmful to some hypertension-prone subjects. The hemodynamic effects of chronic coffee and caffeine consumption have not been sufficiently studied. The possible mechanisms of the cardiovascular effects of caffeine include the blocking of adenosine receptors and the inhibition of phosphodiesterases.

Effect of long-term intake of milk products on blood pressure in hypertensive rats

The effect of long-term intake of two fermented milk products on the development of hypertension was compared in young spontaneously hypertensive rats (SHR). The products contained tripeptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP), which have been shown to possess angiotensin converting enzyme (ACE) inhibitory activity. Six-week-old SHR were divided into four groups to receive orally ad libitum water, skim milk or two fermented milk poducts (fermented milk A or fermented milk B; the latter is commercially available in Japan with trade name Calpis) for 14 weeks. The calculated intake of IPP was 0.4 mg/d and 0.2 mg/d in the groups receiving fermented milk A and B, respectively, whereas the corresponding amounts for VPP were 0.6 mg/d and 0.3 mg/d. Systolic blood pressure (SBP) was monitored weekly by tail-cuff method. The development of hypertension was significantly attenuated in both groups receiving fermented milk products, whereas skim milk did not affect blood pressure. The effect was detectable after 6 weeks of treatment. At the end of the experiment, the lowest blood pressure level was found in the group receiving fermented milk A: the SBP was 21 mm Hg lower than in the group receiving water and 10 mm Hg lower than in the group receiving fermented milk B. This difference could be explained by larger intake of ACE inhibitory tripeptides in the group receiving fermented milk A as compared with fermented milk B.

α-Lactorphin lowers blood pressure measured by radiotelemetry in normotensive and spontaneously hypertensive rats

Abstract Cardiovascular effects of subcutaneous administration of synthetic α-lactorphin, a tetrapeptide (Tyr-Gly-Leu-Phe) originally derived from milk α-lactalbumin, were studied in conscious spontaneously hypertensive rats (SHR) and in normotensive Wistar Kyoto rats (WKY) with continuous radiotelemetric monitoring. α-Lactorphin dose-dependently lowered blood pressure (BP) without affecting heart rate in SHR and WKY. The lowest dose which reduced BP was 10 μg/kg, and the maximal reductions in systolic and diastolic BP (by 23 ± 4 and 17 ± 4 mm Hg, respectively) were observed at 100 μg/kg dose in SHR. No further reductions were obtained at a higher dose of 1 mg/kg. There were no significant differences in the BP responses to α-lactorphin between SHR and WKY. Naloxone (1 and 3 mg/kg s.c.), a specific opioid receptor antagonist, abolished the α-lactorphin-induced reduction in BP and reversed it into a pressor response, which provides evidence for an involvement of opioid receptors in the depressor action of the tetrapeptide.

α-lactorphin and β-lactorphin improve arterial function in spontaneously hypertensive rats

alpha-lactorphin (Tyr-Gly-Leu-Phe) lowers blood pressure in conscious adult SHR. This tetrapeptide is originally released from milk protein alpha-lactalbumin by enzymatic hydrolysis. In order to evaluate the antihypertensive mechanisms of alpha-lactorphin, the effects of the tetrapeptide on vascular function were investigated in (30-35 weeks old) spontaneously hypertensive rats (SHR) with established hypertension and age-matched normotensive Wistar-Kyoto (WKY) rats in vitro. In addition, we studied the vascular effects of another structurally related tetrapeptide, beta-lactorphin (Tyr-Leu-Leu-Phe), which originates from milk protein beta-lactoglobulin. Endothelium-dependent relaxation to acetylcholine (ACh) was reduced in mesenteric arterial preparations of SHR as compared to those of WKY. In SHR, the ACh-induced relaxation was augmented by alpha-lactorphin or beta-lactorphin. The role of nitric oxide (NO) is suggested, since this improvement was abolished by the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Simultaneous potassium channel inhibitor tetraethylammonium (TEA) elicited no additional effect on the ACh-induced relaxation. The cyclooxygenase inhibitor diclofenac did not attenuate the augmented ACh relaxation induced by alpha-lactorphin or beta-lactorphin, suggesting that endothelial vasodilatory prostanoids were not involved in the effect of the tetrapeptides. Endothelium-independent relaxation to the NO donor sodium nitroprusside (SNP) was augmented in mesenteric arterial preparations of SHR by simultaneous beta-lactorphin. The tetrapeptides did not alter vascular responses in mesenteric arteries from WKY. In conclusion, both alpha-lactorphin and beta-lactorphin improved vascular relaxation in adult SHR in vitro. The beneficial effect of alpha-lactorphin was directed towards endothelial function, whereas beta-lactorphin also enhanced endothelium-independent relaxation.

Cyclosporine induces myocardial connective tissue growth factor in spontaneously hypertensive rats on high-sodium diet

Background. The introduction of cyclosporine (CsA) has led to an improvement in the prognosis of solid organ transplantation. However, drug-induced hypertension and nephrotoxicity, associated with the development of atherosclerosis and coronary heart disease, still worsen the long-term outcome of CsA-treated patients. Whether the CsA-induced myocardial changes are associated with the induction of connective tissue growth factor (CTGF), a recently found polypeptide implicated in extracellular matrix synthesis, is not known. Methods. Spontaneously hypertensive rats (8–9 weeks old) were treated with CsA (5 mg·kg−1·d−1 subcutaneously) for 6 weeks. The influence of angiotensin-converting enzyme inhibition (enalapril 30 mg·kg−1·d−1 orally) and angiotensin-1 receptor blockade (valsartan 3 and 30 mg·kg−1·d−1 orally) on CsA toxicity was also investigated. Myocardial morphology was examined, and vascular lesions were scored. Localization and the quantitative expression of CTGF, as well as collagen I and collagen III, mRNA were evaluated by in situ hybridization and Northern blot. Results. CsA-induced hypertension and nephrotoxicity were associated with myocardial infarcts and vasculopathy of the coronary arteries. CsA increased myocardial CTGF, collagen I, and collagen III mRNA expressions by 91%, 198%, and 151%, respectively. CTGF mRNA expression colocalized with the myocardial lesions. Blockade of the renin-angiotensin system prevented vascular damage and the CsA-induced CTGF, collagen I, and collagen III mRNA overexpressions in the heart. Conclusions. CsA increases CTGF, collagen I, and collagen III mRNA expressions in the heart. The induction of CTGF gene is mediated, at least in part, by angiotensin II.

Comparison of enalapril and valsartan in cyclosporine A‐induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high‐sodium diet

We compared the effects of the angiotensin converting enzyme (ACE) inhibitor enalapril and the angiotensin AT1 receptor antagonist valsartan in cyclosporine A (CsA)‐induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). SHR (8–9 weeks old) on high‐sodium diet were given CsA (5 mg kg−1d −1 s.c.) for 6 weeks. The rats were treated concomitantly either with enalapril (30 mg kg−1d −1 p.o.) or valsartan (3 or 30 mg kg−1 d −1 p.o.). To evaluate the role of bradykinin in the action of enalapril, some rats received a bradykinin B2 receptor antagonist icatibant (HOE 140, 500 μg kg−1 d −1 s.c.) during the last 2 weeks of enalapril treatment. Blood pressure was recorded every second week by tail cuff method. Renal function was measured by serum creatinine, creatinine clearance and urinary excretion of proteins at the end of the experiment. The activity of the renal kallikrein‐kinin system was estimated by urinary kallikrein excretion. CsA caused hypertension, impaired renal function and induced morphological nephrotoxicity with glomerular damage and interstitial fibrosis. Enalapril and the lower dose of valsartan attenuated the CsA‐induced hypertension to the same extent, while the higher dose of valsartan totally abolished it. Icatibant did not reduce the antihypertensive effect of enalapril. Urinary kallikrein excretion was similar in all groups. Enalapril and valsartan equally prevented the CsA‐induced deterioration of kidney function and morphology. The renin‐angiotensin but not the kallikrein‐kinin system plays a crucial role in CsA‐toxicity during high intake of sodium in SHR.

Dietary factors in the pathogenesis and treatment of hypertension

Data accumulated from epidemiological observations, intervention trials and studies on experimental animals provide a growing body of evidence of the influence of various dietary components on blood pressure. Dietary sodium, usually taken in the form of sodium chloride (common salt), is positively associated with blood pressure, and in many hypertensive patients reduction in sodium intake lowers blood pressure. On the other hand, in certain patients potassium, calcium and magnesium may be protective electrolytes against hypertension. Dietary fats, especially n-3 polyunsaturated fatty acids, may also influence blood pressure, whereas the possible role of other macronutrients, such as proteins and carbohydrates, or vitamins in the regulation of blood pressure is less well understood. Occasional ingestion of coffee transiently increases blood pressure, but the effects of habitual coffee consumption are controversial. Excessive use of alcohol on a regular basis has been associated with elevated blood pressure. It has also been shown in case reports that large amounts of liquorice lead to the development of hypertension. Thus, with appropriate dietary modifications, it is possible to prevent the development of high blood pressure and to treat hypertensive patients with fewer drugs and with lower doses. In some patients antihypertensive medication may not be at all necessary.

Effect of intracerebroventricular and intravenous administratioi of nitric oxide donors on blood pressure and heart rate in anaesthetized rats

1 The effects of nitric oxide (NO) releasing substances, sodium nitroprusside, 3‐morpholino sydnonimine (SIN‐1) and a novel oxatriazole derivative, GEA 3162, on blood pressure and heart rate were studied after peripheral or central administration in anaesthetized normotensive Wistar rats. 2 Given as cumulative intravenous injections, both nitroprusside and GEA 3162 (24–188 nmol kg−1) induced short‐lasting and dose‐dependent decreases in mean arterial pressure, while SIN‐1 decreased blood pressure only slightly even after larger doses (94–3000 nmol kg−1). Heart rate increased concomitantly with the hypotensive effect of the NO‐releasing substances. 3 Cumulative intracerebroventricular administration of GEA 3162 (24–188 nmol kg−1) induced a dose‐dependent hypotension with slight but insignificant increases in heart rate. In contrast, intracerebroventricular nitroprusside induced little change in blood pressure, while a large dose of SIN‐1 (3000 nmol kg−1, i.c.v.) slightly increased mean arterial pressure. However, intracerebroventricular nitroprusside and SIN‐1 increased heart rate at doses that did not significantly affect blood pressure. 4 To determine whether the cardiovascular effects of GEA 3162 were attributable to an elevation of cyclic GMP levels, pretreatments with methylene blue, a putative guanylate cyclase inhibitor, were performed. This substance failed to attenuate the cardiovascular effects of peripherally or centrally administered GEA 3162, suggesting that the effects were independent of guanylate cyclase. 5 In conclusion, the centrally administered NO‐donor, GEA 3162, induced a dose‐dependent hypotensive response without significant changes in heart rate. Furthermore, intracerebroventricular injections of nitroprusside and SIN‐1 increased heart rate without affecting blood pressure. These results suggest that NO released by these drugs may affect central mechanisms involved in cardiovascular regulation independently of cyclic GMP.

Cardioventilator effects of TRH in anaesthetized rats: Role of the brain stem

Cardioventilator responses were studied in anaesthetized rats after injections of TRH into either the lateral (i.c.v. lat) or the fourth (i.c.v. IV) cerebral ventricles. TRH induced a more rapid hypertensive effect i.c.v. IV than i.c.v. lat. Blocking of the cerebral aqueduct abolished the hypertensive and tachypnoeic effects of TRH i.c.v. lat but not those of TRH i.c.v. IV. It is concluded that TRH increased blood pressure and ventilation rate via brain stem structures close to the fourth ventricle.

Effect of moxonidine on blood pressure and sympathetic tone in conscious spontaneously hypertensive rats

The effects of moxonidine on blood pressure, heart rate and sympathetic tone were studied in conscious spontaneously hypertensive rats. Intravenous moxonidine (80 nmol) transiently increased blood pressure without affecting heart rate or splanchnic nerve activity. Moxonidine (20-80 nmol) given into the fourth cerebral ventricle dose-dependently lowered mean arterial pressure, heart rate and sympathetic outflow (maximally by 60 +/- 3 mm Hg, 148 +/- 10 beats min(-1) and 15 +/- 3 microV). Moxonidine was more effective by this route than after the injection into the lateral ventricle. Clonidine (20-80 nmol) produced an initial pressor response after both intracerebroventricular routes of administration. A decrease in blood pressure was observed only when clonidine was given into the fourth ventricle. Clonidine decreased heart rate and splanchnic nerve activity similarly like moxonidine when the substances were given into the fourth ventricle. The data imply that the hypotensive effect of moxonidine is related to central sympathoinhibition. The main site of this action appears to be in the brainstem region.