Journal Logo


Caffeine Increases Renal Renin Secretion in a Rat Model of Genetic Heart Failure

Tofovic, Stevan P.; Kusaka, Hideaki; Rominski, Barbara; Jackson, Edwin K.

Author Information
Journal of Cardiovascular Pharmacology: March 1999 - Volume 33 - Issue 3 - p 440-450
  • Free


It is generally accepted that the effects of pharmacologically relevant concentrations of caffeine (2-10 μM) are mediated by blockade of adenosine receptors (1). There is ample evidence indicating that endogenous adenosine inhibits renin release in response to various stimuli (2) and that this inhibition is mediated by the interaction of endogenous adenosine with A1 receptors (3). Inasmuch as adenosine inhibits renin release by activation of A1 receptors, and caffeine blocks the interaction of adenosine with A1 receptors, it stands to reason that caffeine should increase renal renin secretion.

Over the past several years, substantial evidence has accumulated indicating a significant effect of caffeine on basal renin release and on the renin release response to various stimuli. Prolonged consumption of caffeine not only increased plasma renin activity (PRA) but also increased blood pressure (4-7) in two-kidney, one-clip rats, a model of high-renin hypertension. In another model of high-renin hypertension (suprarenal aortic ligation), caffeine augmented both the increase in blood pressure and PRA after the surgical maneuver (8). Furthermore, caffeine has been shown to augment renin release during salt restriction and after administration of diuretics or vasodilators (9-13). In humans, caffeine acutely increased baseline PRA (14) and potentiated renin-release responses to the vasodilator diazoxide (15). In addition, prolonged administration of caffeine increased baseline PRA in humans (16). In patients with liver cirrhosis (a disease characterized by increased PRA and sympathetic activity), it was reported that abstinence from modest caffeine consumption for 3 days decreased elevated PRA and, in some patients, was accompanied by a decrease in elevated norepinephrine levels (17).

In a recent study (11,18), we further examined the mechanisms by which caffeine augments renin release. Specifically we addressed the question whether, in addition to peripheral (intrarenal) adenosine blockade, caffeine potentiates renin release by a central nervous system mechanism. Taken together, data from those studies support the conclusion that caffeine potentiates renal renin secretion by two mechanisms. Under basal conditions, the effects of caffeine on renal renin secretion are mediated exclusively via blockade of renal adenosine receptors. On the other hand, when sympathetic activity is enhanced, caffeine potentiates sympathetically mediated renin release by abolishing the central sympathoinhibitory effects of adenosine and increasing sympathetic outflow.

The fact that caffeine increases basal renin release as well as potentiates the renin-release response to sympathetic activation raises health concerns regarding caffeine consumption in diseases (congestive heart failure, liver cirrhosis) and during therapeutic procedures (salt restriction, diuretics, vasodilators) that are characterized by both increased renin secretion and sympathetic activity. In particular, congestive heart failure is a major health problem in modern societies in which activation of the renin-angiotensin system is clearly detrimental. Therefore, we conducted a study to investigate the effects of caffeine treatment on neurohumoral status and heart performance in spontaneously hypertensive heart failure (SHHF/Mcc-facp) rats, a genetic model of spontaneous hypertensive dilated cardiomyopathy. First, we examined the acute effects of caffeine on heart performance and neurohumoral status in conscious, 9-month-old, lean SHHFs and age-matched spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) normotensive rats. Next, we investigated the effects of short-term caffeine treatment on neurohumoral status and heart performance in old SHHF/Mcc-facp rats, at age 14 months, a time when the animals begin to develop overt heart failure.



Seven male, 9-month-old SHHF/Mcc-facp rats, weighing 440 ± 10.2 g, were obtained from the colony bred and housed at Genetic Models Inc. (Indianapolis, IN, U.S.A.). Seven 9-month-old SHRs (413 ± 5.9 g) and eight 9-month-old normotensive WKY rats (634 ± 11.3 g) were obtained from Taconic Farms (Germantown, NY, U.S.A.). Fifteen aged (14-month-old) male lean SHHF/Mcc-facp rats, weighing 430 ± 11 g (n = 15) were obtained from the colony bred and housed at the Ohio State University Department of Food Science and Technology. Animals were housed in the University of Pittsburgh Animal Care Facility for 2 weeks before being used. Temperature, relative humidity, and the light cycle were kept at 22°C, 55%, and 12 h (7:00 a.m. to 7:00 p.m.) dark/light cycle, respectively. Animals were fed Wayne Rodent Blox 8604 (sodium, 135 mEq/kg, and potassium, 254 mEq/kg; Madison, WI, U.S.A.) and water ad libitum. All experiments were carried out according to the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health.

The SHHF/Mcc-facp rat is a relatively new model of spontaneous heart failure. All animals spontaneously, without any pharmacologic treatment or surgical intervention, develop dilated cardiomyopathy. The cardiac hypertrophy is noticeable as early as age 12 weeks and is fully developed at age 5-6 months (19-21). The lean male SHHF rats die of overt congestive heart failure at the age of 15-18 months. The development of heart failure in SHHF rats is associated with increased blood pressure in a range (20) similar to that observed in the SHR (22). However, the SHHF/Mcc-facp rats are genetically predisposed to develop hypertensive heart failure at an incidence of 100% compared with <20% in SHRs. With the onset of severe heart failure in SHHF/Mcc-facp rats, blood pressure tends to return to normotensive levels. Compared with age-matched normotensive and SHRs, lean male SHHF rats have increased PRA (23,24). Moreover, PRA, atrial natriuretic peptide, and aldosterone levels progressively increase with age, and progression of heart failure (24) and the changes in the neurohumoral status are accompanied by increased urinary protein excretion (21).

Protocol I: Acute effects of caffeine

Before undergoing surgery, animals were placed in standard metabolic cages for 2 days, and 24-h food and water intake and urine volume were measured. Urine samples were analyzed for creatinine, protein, sodium, and potassium concentrations. Urinary and plasma electrolytes and creatinine were measured by flame photometry (model IL943 flame photometer; Instrumentation Laboratory, Lexington, MA, U.S.A.) and creatinine analyzer (Creatinine Analyzer 2; Beckman Instruments, Inc., Fullerton, CA, U.S.A.), respectively. Urine protein was determined by using the Sigma Diagnostics Total Protein kit (Sigma, St. Louis, MO, U.S.A.).

Next, each rat was anesthetized with pentobarbital and placed on a Deltaphase Isothermal pad (Braintree Scientific, Braintree, MA, U.S.A.) to maintain body temperature at 37 ± 0.5°C. The right jugular vein and right carotid artery were exposed through a midline ventral neck incision and completely dissected from surrounding tissue. The right jugular vein was cannulated with PE-50 catheter that was filled with 10% heparin solution and flushed 3-4 times a day to avoid clotting. To assess left ventricular performance in situ, a PE-50 catheter connected to a Digi-Med Heart Performance Analyzer (HPA-200, or HPA-200t; Micro-Med Inc., Louisville, KY, U.S.A.) was advanced by the way of the right carotid artery into the left ventricle. The catheters were tunneled subcutaneously to the back of the neck and protected with a jacket-tether swivel system (Medical Arts, Los Angeles, CA, U.S.A.). After the rats regained consciousness, they could move freely in the cage and had free access to food and tap water. Animals were allowed to recover for 24 h, during which period heart performance variables were continuously monitored and 10-min average values recorded. In this regard, six pressure-time variables were measured: ventricular minimal diastolic pressure (VMDP), ventricular end diastolic pressure (VEDP), ventricular peak systolic pressure (VPSP), heart rate (HR), maximal dP/dt during ventricular contraction (+dP/dtmax), and maximal negative dP/dt during the ventricular relaxation (−dP/dtmax). The following day, basal heart-performance parameters were recorded, and 1.5 ml of arterial blood was withdrawn (carotid artery) for measurement of PRA and catecholamines. The blood volume was replaced by infusing an equal volume of 0.9% saline. Next, a bolus dose of caffeine (10 mg/kg; Sigma Chemical) was slowly injected (0.3 ml/min) and intravenous infusion of caffeine (150 μg/min/50 μl) started. Previously we showed that the dose of caffeine used in this study attenuated the bradycardic and hypotensive effects of exogenous adenosine (11). Specifically, caffeine shifted the adenosine-MABP and the adenosine-HR dose-response curves to the right fivefold and 10-fold, respectively. More important, in normotensive Sprague-Dawley rats, caffeine administered in the previously mentioned dose increased basal PRA, as well as renin-release response to hydralazine (11).

Heart-performance parameters were continuously monitored at 1-min intervals. Forty minutes later, the i.v. infusion was stopped, and blood samples taken for measurement of PRA and catecholamines.

Protocol II: Effects of short-term caffeine treatment

Animals were placed in standard metabolic cages for 2 days before 24-h food and water intake and urine volume were measured under basal conditions. Urine samples were analyzed for creatinine, protein, and sodium and potassium concentrations. A volume of 0.5 ml of blood was drawn from the tail vein for determination of plasma creatinine, potassium, and sodium concentrations. Urine and plasma samples were analyzed as described earlier.

Animals were randomized to drink either water (control group, n = 7) or water containing 0.1% caffeine (caffeine group, n = 8). The selected dose of caffeine (1 g/L in drinking water) previously was shown (4) significantly to attenuate depressor responses to adenosine and to provide plasma caffeine levels of ∼10 μg/ml (plasma concentrations produced by moderate caffeine consumption in humans). After 10 days of treatment, the amount of food and water intake were determined, and 24-h urine samples were collected again for determination of urine volume and protein, creatinine, sodium, and potassium concentrations. The following day, short-term studies were conducted to determine left ventricular performance in situ. Hemodynamic parameters [mean blood pressure, HR, renal blood flow (RBF), renal vascular resistance] and renal excretory parameters (glomerular filtration rate, urine flow, filtration fraction, sodium and potassium excretion rate, and fractional excretions of sodium and potassium), which can affect the renal renin secretion, were determined.

In brief, rats were anesthetized with pentobarbital (50 mg/kg, i.p.), and a heat lamp was positioned above the animal. The body temperature was maintained at 37 ± 0.5°C by adjusting the position of the lamp above the animal. Body temperature was monitored by a rectal temperature probe (Electro-therm, TM99A; Cooper Instrument Corp., Middlefield, CT, U.S.A.). The animal's trachea was cannulated (PE-240) to maintain a patent airway, and two polyethylene catheters (PE-50) were inserted into the left jugular vein. One catheter was used for administration of supplementary boluses of anesthetic, and the second was used for infusion of [14C]inulin.

An additional polyethylene cannula (PE-50) was inserted into the left femoral artery and connected to a Micro-Med digital blood pressure analyzer (Micro-Med) for continuous monitoring of mean arterial blood pressure (MAP) and HR. The blood pressure analyzer was set to time-average MAP and HR at 1-min or 5-min intervals (printer) and 5-s intervals (digital display).

To assess left ventricular performance in situ, a PE-50 catheter connected to a Digi-Med Heart Performance Analyzer (HPA-100; Micro-Med) was advanced by the way of the right carotid artery into the left ventricle. Ten pressure-time variables were measured: VMDP, VEDP, VPSP, HR, maximal dP/dt during ventricular contraction (+dP/dtmax), ventricular pressure at +dP/dtmax (P at +dP/dtmax), "pressure normalized" +dP/dtmax (dP/dt/P), ventricular pressure at maximal dP/dt/P (Pmax at dP/dt/P), maximal negative dP/dt during the ventricular relaxation (−dP/dtmax), and ventricular pressure at −dP/dtmax (P at −dP/dtmax). The measured variables were displayed at 5-s intervals and printed at 1-min intervals. Animals were allowed to recover for 30 min before basal values were recorded for 20 min.

Next, the animal's abdominal cavity was opened with a midline incision, and the right kidney removed. The left ureter was then cannulated (PE-10) for continuous collection of urine. A transit-time blood-flow probe (model T206; Transonic System Inc., Ithaca, NY, U.S.A.) was placed around the left renal artery to monitor continuously RBF. A 22-gauge needle was placed into the left renal vein for sampling of renal venous blood, and an i.v. infusion of inulin [carboxyl-14C] (0.75 μCi bolus followed by 0.05 μCi/min infusion) was commenced. Animals were allowed to stabilize for 45 min before 30-min urine samples were collected into preweighed microfuge tubes. Twenty microliters of urine from these samples was placed in a scintillation vial to measure 14C radioactivity with a liquid scintillation analyzer (model 2500TR; Packard Instrument Company, Downers Grove, IL, U.S.A.). The remaining urine was used to measure the urinary concentration of creatinine, sodium, and potassium, as described earlier. At the midpoint of the clearance period, a 0.5-ml arterial blood sample was collected for measurement of hematocrit, plasma 14C radioactivity, and plasma sodium, potassium, and creatinine. At the end of the urine collection, 1.0 ml of arterial (femoral artery) and venous (renal vein) blood was withdrawn for measurement of PRA and catecholamines.

Plasma renin activity analysis

PRA was determined by using the Rainen Angiotensin I [125I] RIA Kit (Du Pont NEN Research Products, Boston, MA, U.S.A.) with appropriate modifications and validations (3). PRA was expressed as nanograms angiotensin I generated/ml/hour and was calculated by the RIASmart Software Package (Packard Instrument, Meridan, CT, U.S.A.) by using a weighted LOGIT analysis program. Intraassay precision (coefficient of variation, CV) was <10%, and interassay CV, calculated from the means of identical samples analyzed by three different batches of kits, was <15%. The renal renin secretion was calculated by subtracting the arterial level of PRA from the renal vein level and multiplying the difference by renal plasma flow.

Catecholamine analysis

Catecholamines were assayed by high-performance liquid chromatography with electrochemical detection. For sample analysis, a commercial ESA Plasma Catecholamine Analysis Kit (ESA Inc., Bedford, MA, U.S.A.) was used. To monitor recovery, an internal standard (DHBA) was added to each sample. The chromatographic system was composed of an Isco (Lincoln, NE, U.S.A.) pump (model 2350) and gradient programmer (model 2360), and ChemResearch Data Management System (Isco), along with an ESA Catecholamine HR-80 Column and Coulochem Electrochemical Detector (model 5200; ESA).

Statistical analysis

Results are presented as mean ± SEM. Statistical analyses were performed by using the Number Crunchers Statistical System (Kaysville, UT, U.S.A.). Group comparisons were done by one- (1F) and two-way (2F) nested (hierarchic) analysis of variance (ANOVA) as appropriate. If this analysis indicated a significant difference among the means, specific comparison were made with a Fisher's LSD test.


Protocol 1: Acute effects of caffeine in conscious WKY rats, SHRs, and SHHF/Mcc-facp rats

Baseline values for metabolic parameters are presented in Table 1. Significant increases in food intake, urine volume, and sodium, potassium, and creatinine excretion were found in SHHF/Mcc-facp rats compared with age-matched WKY rats and SHRs (1-F ANOVA, p < 0.05). SHHF/Mcc-facp rats exhibited significant renal dysfunction, as evidenced by a reduction in creatinine clearance (5.5 ± 1.5 vs. 7.2 ± 0.82, SHHF vs. WKY rats; p < 0.05) and a significantly increased urinary protein excretion (572 ± 58.1, 58.2 ± 8.7, and 93.1 ± 8.2, for SHHF, WKY rats, and SHRs, respectively; p < 0.001, 1F-ANOVA).

Baseline values for metabolic study in 9-month-old WKY, SHR, and SHHF/Mcc-fa cp animals

The assessment of left ventricular function in conscious animals (Table 2) under basal condition, revealed no differences in left ventricular contractility (+dP/dtmax) or diastolic function (−dP/dtmax) in SHHF/Mcc-facp rats compared with age and blood pressure-matched SHRs. However, significantly increased VEDP and VMDPs were registered in SHHF/Mcc-facp rats (1F-ANOVA: p < 0.001), suggesting early left ventricular dysfunction in hypertensive heart failure-prone animals.

Baseline values for heart function in conscious WKY, SHR, and SHHF/Mcc-fa cp animals

Caffeine infusion (10 mg/kg + 150 μg/min) increased HR in SHHF rats and SHRs but not in WKY rats (Fig. 1, top). Also, in hypertensive (SHHF rats and SHRs) but not in normotensive (WKY) animals, caffeine produced a transient increase in VPSP (Fig. 1, bottom). In all three strains, during caffeine infusion, no significant changes from baseline were found for +dP/dtmax, −dP/dtmax, VEDP, and VMDP (Figs. 2 and 3). Pressure-normalized +dP/dt, a more accurate index of cardiac contractility, was not different among the three strains, and caffeine had no effects on cardiac contractility (Fig. 4, bottom). However, in both SHRs and SHHF rats but not in WKY rats, caffeine increased heart workload (HR × VPSP product; Fig. 4, top).

FIG. 1
FIG. 1:
Acute effects of caffeine on heart rate and ventricular peak systolic pressure (VPSP) in conscious Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs), and spontaneously hypertensive heart failure (SHHF/Mcc-fa cp) rats (1F-ANOVA, p < 0.05; a, vs. baseline, SHHF rats; b, vs. baseline, SHRs).
FIG. 2
FIG. 2:
Acute effects of caffeine on maximal dP/dt during ventricular contraction and relaxation (+dP/dtmax and −dP/dtmax, respectively) in conscious Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs), and spontaneously hypertensive heart failure (SHHF/Mcc-fa cp) rats.
FIG. 3
FIG. 3:
Acute effects of caffeine on ventricular end-diastolic pressure (VEDP) and ventricular minimal diastolic pressure (VMDP) in conscious Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs), and spontaneously hypertensive heart failure (SHHF/Mcc-fa cp) rats.
FIG. 4
FIG. 4:
Acute effects of caffeine on heart rate-ventricular peak systolic pressure product (HR × VPSP) and pressure-normalized +dP/dtmax (+dP/dtmax/VPSP) in conscious Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs), and spontaneously hypertensive heart failure (SHHF/Mcc-fa cp) rats (1F-ANOVA, p < 0.05; a, vs. baseline SHHF rats; b, vs. baseline SHRs; c, vs. baseline WKY rats).

The effects of caffeine on renin secretion are shown in Fig. 5. Caffeine increased PRA in all strains (treatment effect: p < 0.001, 2F-ANOVA). The baseline PRA levels in SHHF rats determined in this study tended to be higher as compared with WKY rats and were similar to previously reported values for conscious, 12-month-old, male, lean SHHF rats (24). In this study, SHRs had similar levels of PRA as compared with SHHF rats. In both SHRs and SHHF rats, caffeine induced greater renin responses (PRA changes from the baseline values) as compared with normotensive WKY rats (p < 0.015; 1F-ANOVA).

FIG. 5
FIG. 5:
Acute effects of caffeine on plasma renin activity (PRA) in conscious Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs), and spontaneously hypertensive heart failure (SHHF/Mcc-fa cp) rats (2F-ANOVA, p < 0.05; a, vs. baseline; b, vs. WKY rats; c, vs. SHHF rats).

Under baseline conditions, SHHF rats tended to have higher plasma norepinephrine levels compared with SHRs and WKY rats, but this difference did not reach statistical significance (Fig. 6). Caffeine increased plasma NE levels in all three strains (treatment effects: p < 0.001; 2F-ANOVA), but this effect was greater in SHHF rats as compared with normotensive WKY rats (1,025.8 pg/ml vs. 604.7 pg/ml; p < 0.05, Fisher's LSD test). SHHF rats had higher basal epinephrine plasma levels compared with SHRs and WKY rats (strain effects: p < 0.015; 1F-ANOVA; Fig. 7). Caffeine increased plasma epinephrine levels (p < 0.001, 2F-ANOVA), and this effect was significantly greater in hypertensive animals (SHRs and SHHF rats) than in WKY rats (p < 0.05, Fisher's LSD test). When expressed as percentage changes from the baseline (data not shown), caffeine induced significantly greater changes in epinephrine in SHRs compared with SHHF and WKY rats (p < 0.05, Fisher's LSD test).

FIG. 6
FIG. 6:
Acute effects of caffeine on plasma norepinephrine in conscious Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs), and spontaneously hypertensive heart failure (SHHF/Mcc-fa cp) rats (1F-ANOVA: a, vs. baseline; b, vs. WKY rats).
FIG. 7
FIG. 7:
Acute effects of caffeine on plasma epinephrine in conscious Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs), and spontaneously hypertensive heart failure (SHHF/Mcc-fa cp) rats (1F-ANOVA; a, vs. baseline; b, vs. WKY rats; c, vs. WKY rats and SHRs).

Protocol 2: Effects of short-term caffeine treatment

After 10 days of caffeine treatment, no changes in metabolic parameters (body weight, food and water intake, urine volume, protein, sodium, and potassium excretion, creatinine clearance, and fractional excretion of sodium and potassium) were found in caffeine-treated animals compared with the control group [(data not shown) 2F-ANOVA with repeated measures]. During the treatment, one animal in the caffeine-treated group died of overt congestive heart failure (obvious pulmonary exudate and extremely dilated heart). Signs of self-biting were noted in the chest area in this animal. It was reported that high doses of caffeine induce self-biting in rats (25), and therefore this phenomenon might be explained by high plasma levels of caffeine due to decreased hepatic clearance during overt congestive heart failure. Two additional animals in the caffeine-treated group and one animal in the control group died before the end of the protocol, and the total mortality was one of seven in the control group compared with three of eight in the caffeine-treated group.

No significant differences were found with respect to heart weight, heart/body weight, heart/brain weight ratios, and measured cardiac time-pressure variables (Table 3). In both control and caffeine-treated SHHF/Mcc-facp rats, decreased heart performance was observed. Both significantly (p < 0.05) increased VEDP and decreased +dP/dt were registered in the aged (14 months old) SHHF rats as compared with both adult, 9-month-old SHHF rats (Protocol 1, Table 1), as well as with values in aged SHRs (+dP/dt = 10,425 ± 1,391 mm Hg/s; +dP/dt/P = 448 ± 106/s; VEDP = −0.9 ± 3.6 mm Hg) found in our previous study (26). Because of the within-group variability, no conclusion could be drawn as to the short-term effects of caffeine on heart performance in these aged rats (Table 3). However, a tendency toward decreased contractility was suggested in the caffeine group by using nonparametric test (p < 0.167, Mann-Whitney test).

Heart function in anesthetized, 14-month-old SHHF/Mcc-fa cp rats after 10-day caffeine treatment

Table 4 lists MABP, HR, and renal parameters that can affect renin secretion (RBF, glomerular filtration rate, urine flow, filtration fraction, sodium and potassium excretion rate, and fractional excretions of sodium and potassium) for both the control and caffeine-treated groups. These data were analyzed with 1F-ANOVA, and no statistically significant differences were found between the caffeine group and control group values for all measured hemodynamic and renal parameters, thus excluding these parameters from differently altering renal renin secretion in the control vs. the caffeine-treated group.

Hemodynamic and renal excretory function in anesthetized, 14-month-old SHHF/Mcc-fa cp rats after 10-day caffeine treatment

PRA values in venous (renal vein) and arterial blood (femoral artery) after 10 days of treatment with caffeine are presented in Fig. 8 (left axis). Caffeine treatment tended to increase PRA in both arterial and venous blood, but this increase did not reach statistical significance. More important, renal renin secretion (Fig. 8, right axis) was increased significantly in caffeine-treated animals compared with control animals (71.1 ± 19.2 vs. 9.5 ± 5.8 ng Ang I/h/min/kg, respectively; p < 0.01).

FIG. 8
FIG. 8:
Effects of short-term (10 days) caffeine on plasma renin activity (PRA) in arterial and renal venous blood samples (left axis) and renal renin secretion (right axis).

Significantly higher baseline plasma levels of norepinephrine (NE) and epinephrine (E) were found in 14-month-old SHHF rats (NE = 1,650 ± 301 and 998 ± 149 pg/ml; E = 2,306 ± 814 and 1,739 ± 558 pg/ml, for control and caffeine group, respectively), as compared with adult, 9-month-old animals (Protocol 1, Figs. 6 and 7). Increased baseline catecholamine levels may be explained by progression of heart failure in SHHF rats, because at that age (15-18 months), animals begin to develop and eventually die of overt congestive heart failure. Short-term caffeine treatment did not alter the increased baseline plasma catecholamine levels.


There is strong evidence that caffeine, by blocking intrarenal adenosine receptors, increases renin secretion both under basal conditions and in response to various stimuli (supra vide). Moreover, caffeine increases peripheral and central sympathetic tone (14,18,27-31), and recently we demonstrated that caffeine augments sympathetically mediated renin release, in part by increasing sympathetic tone (11,18). We thought it important to investigate the cardiovascular and renal effects of caffeine consumption in an experimental spontaneous heart failure model for two clinically relevant reasons. First, activation of both the sympathetic nervous system and the renin-angiotensin system participate in the morbidity and mortality associated with congestive heart failure. As heart failure progresses, the activity of these two vasoconstrictor and sodium-retaining systems increases and contributes to the decline in cardiac function (32). Second, most common clinical treatment plans in heart failure (e.g., salt restriction, diuretics, vasodilators) increase both PRA and sympathetic activity. Thus caffeine consumption may alter the natural history of heart failure or the response to therapeutic interventions or both by activating the renin-angiotensin and sympathetic systems. Accordingly, we investigated the effects of both acute caffeine administration and short-term caffeine treatment on neurohumoral status and heart performance in SHHF/Mcc-facp rats, a genetic model of spontaneous hypertensive cardiomyopathy. We used both adult (age 9 months) and old (age 14 months) lean male SHHF/Mcc-facp rats. The older animals had established heart failure and were at an age when mortality from overt heart failure is high (15-18 months).

Although +dP/dt was preserved in adult (9-month-old) SHHF rats as compared with age-matched SHRs and WKY rats, VEDP and VMDP were increased in SHHF rats, suggesting mild left ventricular dysfunction. The left ventricular dysfunction in SHHF rats was associated with neurohumoral activation (increased PRA, NE, and E) as compared with normotensive WKY rats. Surprisingly, in this study, in contrast to previously reported data (24), increased PRA values also were found in SHRs. The possible explanation for the unexpected high levels of PRA in SHRs is that, under the condition of this study, SHRs were more stressed than WKY and SHHF rats. Significantly higher HRs and the largest epinephrine response to caffeine infusion were found in SHRs as compared with WKY and SHHF rats.

Caffeine infusion increased PRA in all three strains, and this increase in renin secretion was accompanied by increased plasma catecholamine levels. This suggests that acute effects of caffeine on renin release in conscious animals may be due in part to increased central sympathetic tone, a conclusion consistent with previous studies (11,14,18,27-31). The neurohumoral activation was greater in hypertensive (SHHF rats and SHRs) than in normotensive (WKY) animals and was accompanied by increased workload (heart rate-pressure product). Greater hemodynamic and neurohumoral responses to caffeine in old hypertensive animals (SHRs and SHHF rats) may be explained by a different rate of adenosine biosynthesis or a different sensitivity to exogenous adenosine or both in hypertensive animals in comparison with normotensive WKY rats. For instance, increased plasma levels of adenosine have been reported in SHRs compared with age-matched WKY rats (33). In addition, aged rats have higher interstitial cardiac adenosine concentration (34,35) and adenosine-induced inhibition of lipolysis, HR, and renin-release increases with age (36,37). Therefore, blockade of adenosine receptors by caffeine would have a greater effect on heart workload and neurohumoral status in old hypertensive SHRs and SHHF rats compared with normotensive WKY rats.

Neurohumoral activation and increased workload, in the absence of any effects on cardiac contractility (supra vide), suggest that caffeine may adversely affect heart function in hypertensive cardiomyopathy. For many years, it was widely held that tolerance to the pressor response occurs after repeated caffeine administration (38). However, recent studies in humans indicated that caffeine increases blood pressure in habitual coffee drinkers after an overnight abstinence in normotensive regular coffee drinkers (39), that the pressure response to caffeine is larger in borderline hypertensives than in normotensive controls (40), and that caffeine increases blood pressure and places a greater workload on the heart (rate-pressure product) in response to exercise in the mild hypertensive population (41). The results of our study underscore the need to determine the health consequences of the pressor and neurohumoral response to long-term caffeine consumption in heart failure.

In 14-month-old SHHF rats with advanced heart failure, 10-day caffeine treatment did not produce statistically significant differences between treated and control animals with regard to measured hemodynamic and renal-excretory parameters that can affect renal renin secretion. No changes in plasma catecholamine levels were found. Thus in this study, we were able to exclude the influence of possible caffeine-induced changes in hemodynamics, renal excretory function, or sympathetic activity (or a combination of these) on renal renin secretion. Nonetheless, renin release was increased in the caffeine-treated group, suggesting that the increased renal renin secretion induced by caffeine was due to blockade of intrarenal adenosine receptors. This is consistent with our previous results (11,18) showing that under basal conditions, caffeine increases renin secretion by blockade of peripheral (intrarenal) adenosine receptors.

In this study we also evaluated the effects of short-term caffeine treatment on cardiac performance in vivo. There is a plethora of data related to caffeine's effects on heart function in vitro (42-44). However, those data are inconsistent, and their physiological relevance is questionable because those studies used much higher concentrations (1-20 mM) of caffeine than those attained during human caffeine consumption. At these high concentrations, caffeine was shown to inhibit cardiac phosphodiesterase, or alter intracellular release of calcium or both. In contrast to the in vitro studies, there are limited experimental data regarding the effects of prolonged or short-term caffeine ingestion on myocardial function in vivo. Lifetime ingestion of caffeine (0.1%) was reported (45) to reduce life span significantly in rats because of myocardial insufficiency (i.e., myocardial fibrosis). Prolonged caffeine consumption during early growth (from birth until the age of 12 weeks) was reported to impair cardiac performance in rats (46,47). Surprisingly, there are no experimental or clinical data regarding the effects of caffeine in heart failure. Therefore, we studied the effects of caffeine on cardiac performance in vivo. In this regard, short-term caffeine treatment did not significantly alter cardiac performance in aged SHHF/Mc-facp rats; however, long-term studies are needed to elucidate the possible detrimental effects of caffeine on cardiac performance in heart failure.

In summary, acute administration of caffeine increases cardiac workload and activates the renin-angiotensin and sympathetic nervous systems in heart failure. Moreover, this study provides the first evidence that short-term caffeine consumption increases renal renin secretion in heart failure, an effect that is most likely due to blockade of intrarenal adenosine receptors. Given the well-known adverse effects of angiotensin II in heart failure, additional studies are warranted to determine whether long-term caffeine administration increases morbidity and mortality in experimental heart failure.

Acknowledgment: This work was supported by grants from the National Institutes of Health (HL55314 and HL35909).


1. Daly J. Mechanism of action of caffeine. In: Garattini S, ed. Caffeine, coffee and health. New York: Raven Press, 1993:97-124.
2. Jackson EK. Adenosine: A physiological brake on renin release. Annu Rev Pharmacol Toxicol 1991;31:1-35.
3. Pfeiffer CA, Suzuki F, Jackson EK. Selective A1 but not A2 adenosine receptor antagonism augments β-adrenergic-induced renin release in vivo. Am J Physiol 1995;269:F469-79.
4. Ohnishi A, Branch RA, Jackson K, Biaggioni I, Deray G, Jackson EK. Chronic caffeine administration exacerbates renovascular but not genetic hypertension in rats. J Clin Invest 1986;78:1045-50.
5. Kohno M, Murakawa K, Horio T, et al. Plasma immunoreactive endothelin-1 in experimental malignant hypertension. Hypertension 1991;18:93-100.
6. Choi KC, Lee J, Moon KH, Park KK, Kim SW, Kim NH. Chronic caffeine ingestion exacerbates 2-kidney, 1-clip hypertension and ameliorates deoxycorticosterone acetate-salt hypertension in rats. Nephron 1993;65:619-22.
7. Kost CC, Li P, Pfeiffer CA, Jackson EK. Telemetric blood pressure monitoring in benign 2-kidney, 1-clip renovascular hypertension: effect of chronic caffeine ingestion. J Pharmacol Exp Ther 1994;270:1063-1070.
8. Ohnishi A, Li P, Branch RA, Biaggioni IO, Jackson EK. Adenosine in renin-dependent renovascular hypertension. Hypertension 1988;12:152-61.
9. Paul S, Jackson EK, Robertson D, Branch RA, Biaggioni I. Caffeine potentiates the renin response to furosemide in rats: evidence for a regulatory role of endogenous adenosine. J Pharmacol Exp Ther 1989;251:183-7.
10. Kuan CJ, Wells JN, Jackson EK. Endogenous adenosine restrains renin release in conscious rats. Circ Res 1990;66:637-46.
11. Tofovic SP, Branch KR, Oliver RD, Magee WD, Jackson EK. Caffeine potentiates vasodilator induced renin release. J Pharmacol Exp Ther 1991;256:850-60.
12. Tung CS, Kuan CJ, Tang JL, Tseng CJ. Effects of adenosine blockade on plasma renin activity and catecholamines. Proc Natl Sci Repub China 1993;17-B:21-8.
13. Tseng CJ, Kuan CJ, Chu H, Tung CS. Effect of caffeine treatment on plasma renin activity and angiotensin I concentrations in rats. Life Sci 1993;52:883-90.
14. Robertson D, Frolich JC, Carr RK, et al. Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med 1978;298:181-6.
15. Brown NJ, Ryder D, Nadeau J. Caffeine attenuates the renal vascular response to angiotensin II infusion. Hypertension 1993;22:847-52.
16. Brown NJ, Porter J, Ryder D, Branch RA. Caffeine potentiates the renin response to diazoxide in man: evidence for a regulatory role of endogenous adenosine. J Pharmacol Exp Ther 1991;256:56-61.
17. Hasegawa M, Yamada S, Hirayama C. Fasting plasma caffeine level in cirrhotic patients: relation to plasma levels of catecholamines and renin activity. Hepatology 1989;10:973-7.
18. Tofovic SP, Kusaka H, Pfeifer CA, Jackson EK. Central effects of caffeine on renal renin secretion and norepinephrine spillover. J Cardiovasc Pharmacol 1996;28:302-13.
19. McCune SA, Jenkins JE, Stills HF, et al. Renal and heart function in the SHHF/Mcc-cp rat in frontiers in diabetes research. In: Shafrir E, ed. Lesson from animal diabetes II. London: Smith-Gorden, 1991:397-401.
20. McCune SA, Radin JM, Jemkins JE, Chu Y-Y, Park S, Peterson R. SHHF/Mcc-facp rat model. Effects of gender and genotype on age of expression of metabolic complication and congestive heart failure and on response to drug therapy. In: Shafrir E, ed. Frontiers in diabetes research: lesson from animal diabetes V. London: Smith-Gorden, 1994:255-70.
21. McCune SA, Park S, Radin JM, Jurin RR. The SHHF/Mcc-facp: a genetic model of congestive heart failure. In: Singal PK, Dixon IMC, Beamish RE, Dhalla MS, eds. Mechanisms of heart failure. Boston: Kluwer Academic Publishers, 1995:91-106.
22. Pfeffer JM, Pfeffer MA, Braunwald E. Alterations in cardiac performance in rats with established spontaneous hypertension. Am J Cardiol 1979;44:994-8.
23. Dunn RB, McCune SA, Summers B. Suppressive effects of ANF infusion on renin and aldosterone in congestive heart failure prone rats (Mcc:SHR-cp obese hypertensive substrain). FASEB J 1988;2:A525.
24. Holycross BJ, Summers BM, Dunn RB, McCune SA. Plasma renin activity in the heart failure prone SHHF\Mcc-facp rats. Am J Physiol 1997;273:H228-33.
25. Minana MD, Grisolia S. Caffeine ingestion by rats increases noradrenaline turnover and results in self-biting. J Neurochem 1986;47:728-32.
26. Tofovic SP, Kost CK, Li P, Jackson EK. Heart and kidney function in adult ZDF × SHHF (Hybrid)-fa/facp rats. FASEB J 1995;A53:306.
27. Henry JP, Stephens PM. Caffeine as an intensifier of stress-induced hormonal and pathophysiologic changes in mice. Pharmacol Biochem Behav 1980;13:719-22.
28. Smits P, Horman H, Thien T, Houben H, Van't Laar A. Hemodynamic and humoral effects of coffee after beta-selective and nonselective beta-blockade. Clin Pharmacol Ther 1983;34:153-8.
29. Lane JD, Adcock RA, Williams RB, Kuhn CM. Caffeine effects on cardiovascular and neuroendocrine responses to acute psychosocial stress and their relationship to level of habitual caffeine consumption. Psychosom Med 1990;52:320-36.
30. Mosqueda-Garcia R, Killian TJ, Haile V, Tseng C-J, Robertson RM, Robertson D. Effects of caffeine on plasma catecholamines and muscle sympathetic nerve activity in man. Circulation 1990;82:III-335.
31. Kerr D, Sherwin RS, Pavalkis K, et al. Effects of caffeine on the recognition of and responses to hypoglycemia in humans. Ann Intern Med 1993;119:799-804.
32. Francis GS. Neuroendocrine activity in congestive heart failure. Am J Cardiol 1989;66(suppl D):33D-9D.
33. Yamada K, Goto A, Ishii M, Yosioka M, Matsuoka H, Sugimoto T. Plasma adenosine concentrations are elevated in conscious spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 1992;19(8):563-7.
34. Dobson JG, Fenton RA, Romano FD. Increased myocardial adenosine production and reduction of beta-adrenergic contractile response in aged rats. Circ Res 1990;66:1381-90.
35. Dobson JG, Fenton RA. Adenosine inhibition of beta-adrenergic induced responses in aged hearts. Am J Physiol 1993;265:H494-503.
36. Hoffman BB, Chang H, Farahbakhah Z, Raeven G. Inhibition of lipolysis by adenosine is potentiated with age. J Clin Invest 1984;74:1750-5.
37. Suteparuk S, Nies A, Andros E, Gerber JG. The role of adenosine in promoting cardiac beta-adrenergic subsensitivity in aging humans. J Gerontol Biol Sci 1995;50A(3):B128-34.
38. Myers MG. Effects of caffeine on blood pressure. Arch Intern Med 1988;148:1189-93.
39. Passmore AP, Kondowe GB, Johnston GD. Renal and cardiovascular effects of caffeine: a dose-response study. Clin Sci 1987;72:749-56.
40. Pincomb GA, Lovallo WR, McKey BS, et al. Acute blood pressure elevation with caffeine in men with borderline systemic hypertension. Am J Cardiol 1996;77:270-4.
41. Sung BH, Lovallo WR, Whitsett T, Wilson MF. Caffeine elevates blood pressure response to exercise in mild hypertensive man. Am J Hypertens 1995;8:1184-8.
42. Blinks JR, Olson CB, Jewell BR, Braveny P. Influence of caffeine and other methylxanthines on mechanical properties of isolated mammalian heart muscle. Circ Res 1972;30:367-92.
43. Di Gennaro M, Vassale M. Role of calcium on the actions of caffeine in ventricular muscle fibers. J Cardiovasc Pharmacol 1984;6:739-47.
44. MacIntosh BR, Posner P, Lobo J, Harmus R. Rat atrial muscle responses with caffeine: dose-response, force frequency, and postrest contractions. Can J Pharmacol 1991;7:275-82.
45. Johansson S. Cardiovascular lesion in Sprague-Dawley rats induced by long-term treatment with caffeine. Acta Pathol Microbiol Scand 1981;89A:185-99.
46. Temples TE, Geoffray DJ, Nakamoto T, Hartman AD, Miller HI. The effects of caffeine intake during early growth and development on cardiac function. Proc Soc Exp Biol Med 1985;179:388-95.
47. Temples TE, Geoffray DJ, Nakamoto T, Hartman AD. Effects of chronic caffeine intake on myocardial function during early growth. Pediatr Res 1987;21:391-5.

Caffeine; Renin secretion; Rat; Heart failure

© 1999 Lippincott Williams & Wilkins, Inc.