Influence of feeding schedules on the chronobiology of renin activity,urinary electrolytes and blood pressure in dogs

The contribution of the renin–angiotensin–aldosterone system (RAAS) to the development of congestive heart failure (CHF) and hypertension (HT) has long been recognized. Medications that are commonly used in the course of CHF and HT are most often given with morning food for the sake of convenience and therapeutic compliance. However, biological rhythms and their responsiveness to environmental clues such as food intake may noticeably impact the effectiveness of drugs used in the management of cardiovascular disorders. Only sparse information about the effect of feeding schedules on the biology of the RAAS and blood pressure (BP) is presently available. Two studies were designed to explore the chronobiology of renin activity (RA), BP, renal sodium (U_Na,fe) and potassium (U_K,fe) handling in relation to meal timing in dogs. In a first experiment (Study a), blood and urinary samples for measurement of RA, U_Na,fe and U_K,fe were drawn from 18 healthy beagle dogs fed a normal-sodium diet at either 07:00, 13:00 or 19:00?h. In a second experiment (Study b), BP was recorded continuously from six healthy, telemetered beagle dogs fed a similar diet at 07:00, or 19:00?h. Data were collected throughout 24-h time periods, and analyzed by means of nonlinear mixed-effects models. Differences between the geometric means of early versus late time after feeding observations were further compared using parametric statistics. In agreement with our previous investigations, the results indicate that RA, U_Na,fe, U_K,fe, systolic, and diastolic BP oscillate with a circadian periodicity in dogs fed a regular diet at 07:00?h. A cosine model with a fixed 24-h period was found to fit the variations of RA, U_K,fe and BP well, whereas cyclic changes in U_Na,fe were best characterized by means of a combined cosine and surge model, reflecting a postprandial sodium excretion followed by a monotonous decay. Our data show that feeding time has a marked influence on the chronobiology of the renin cascade, urinary electrolytes, and BP. Introducing a 6- or 12-h delay in the dogs’ feeding schedule caused a shift of similar magnitude (05:06 and 12:32?h for Studies a and b, respectively) in the rhythm of these biomarkers. In all study groups, RA and BP exhibited a marked fall just after food intake. The drop in RA is consistent with sodium and water-induced body fluid expansion, while the reduction of BP could be related to the decreased activity of renin and the secretion of vasodilatory gut peptides. An approximately 1.5-fold (1.2–1.6-fold) change between the average early and late time after feeding observations was found for RA (p?<?0.0001), U_Na,fe (p?<?0.01) and U_K,fe (p?<?0.05). Postprandial variations in BP, albeit small (ca. 10?mmHg), were statistically significant (p?<?0.01) and supported by the model-based analysis.

In conclusion, the timing of food intake appears to be pivotal to the circadian organization of the renin cascade and BP. This synchronizing effect could be mediated by feeding-related signals, such as dietary sodium, capable of entraining circadian oscillators downstream of the master, light–dark-adjusted pacemaker in the suprachiasmatic nucleus.     

钙通道阻断剂异搏定对缺氧性肺动脉高压形成的影响

为考察Ca~( )在缺氧性肺动脉高压形成中的作用,我们观察了钙通道阻断剂异搏定对慢性连续性缺氧大鼠肺动脉压及左右心功能的影响。将动物置于模拟海拔5000m高原的低压舱内,腹腔注射异搏定,剂量为4mg/kg BW,每日两次。实验结果表明:异搏定可以减弱缺氧15天所引起的肺动脉压升高和右心功能加强的程度,对颈动脉压及左心功能无明显影响,提示Ca~( )的跨膜内流是构成缺氧性肺动脉高压形成的重要基础之一。我们还比较了异搏定对缺氧持续时间不同(15天、10天、5天)的大鼠肺循环的影响,并讨论了异搏定发生作用的机制。     

ACTH 1-24-induced potentiation of norepinephrine contractile responses in aortic strips from spontaneously hypertensive (SH) and normotensive (WKY) rats

Norepinephrine (NE)-induced contractile responses were less in aortic strips from SH compared to WKY rats. ACTH 1-24 potentiated NE responses in both SH and WKY aortic strips. This effect was more potent in SH aortic strips. NE-induced contractions in SH aortic strips were less sensitive to changes in external Ca2+ levels than were those of WKY aortic strips. ACTH 1-24 did not potentiate NE responses under low external Ca2+ conditions in SH aortic strips or under high external Ca2+ conditions in WKY aortic strips. The greater sensitivity of NE responses following ACTH 1-24 in SH aortic strips may imply that this peptide is modulating a mechanism related to an impaired contractility and that Ca2+ plays a key role in the observed effects.     

The efficacy of biobehavioral and compliance interventions in the adjunctive treatment of mild pregnancy-induced hypertension

This investigation assessed the efficacy of a biobehavioral intervention in the adjunctive treatment of mild pregnancy-induced hypertension (PIH), a potentially serious complication of pregnancy in which normotensive women develop hypertension, proteinuria, and edema of unknown etiology late in gestation. Forty-five women with symptoms of PIH were randomly assigned to one of three treatment conditions: bed rest alone (the most common obstetrical treatment), bed rest with individualized compliance enhancement training, or a four-session biobehavioral treatment consisting of bed rest, compliance enhancement training, and individualized thermal biofeedback-assisted relaxation training. Results indicated that while blood pressure for the bed rest and compliance enhancement groups continued to rise and pose an increasing health risk to maternal and fetal well-being, subjects in the biobehavioral group maintained their blood pressure at a significantly lower, and presumably safer, level. The biobehavioral treatment is hypothesized to affect blood pressure levels in subjects with mild PIH through the mediation of the sympathetic nervous system, decreasing peripheral vascular resistance and cardiac output. The results of this investigation suggest that the biobehavioral intervention may be an effective adjunct to bed rest in the treatment of mild PIH remote from term.     

Subjective experiences associated with thermal biofeedback treatment of hypertension

Reports of subjective experiences of 73 hypertensive patients who were treated with thermal biofeedback for hand warming were obtained over 16 treatment sessions. Most of the differential responding in subjective report occurred in the first 5 sessions. Differences in reports of throbbing were associated with medication status during treatment (presence of sympatholytic antihypertensive agent). From 4 to 9% of patients report negative subjective experiences at any one session. When short-term clinical successes (either elimination of medication or reduction of BP) were compared with short-term failures, it was found that successes reported more warmth, more likelihood of falling asleep, and more dreamlike experiences. The latter were more likely to occur suddenly for the successes. Correlational analyses revealed consistent positive associations between reports of warmth and relaxation with highest temperature achieved in the session and consistent negative associations between experiencing physical sensations and degree of temperature change within the session.This research was supported in part by grants from NHLBI, HL-27622 and HL-31189.     

Reduction of cardiac hypertrophy in TGR(mREN2)27 by angiotensin II receptor blockade

TGR(mREN2)27 is a transgenic rat harboring the murine Ren-2 gene and exhibit fulminant hypertension and marked heart hypertrophy. In order to study the role of angiotensin II in the increase of cardiac mass, these animals were treated with anti-hypertensive and non-antihypertensive doses of the angiotensin II receptor AT₁ antagonist Telmisartan for 9 weeks. All doses led to significant reductions of heart hypertrophy detected by the evaluation of the diameter of cardiac muscle bundles. We conclude from this study that cardiac hypertrophy in TGR(mREN2)27 is characterized by an increased volume of cardiomyocytes and an unchanged amount of fibrous tissue and that angiotensin II plays an important role in the mechanisms leading to this phenotype.     

Platelet calcium pump activity in essential hypertensives and their first-degree relatives

Intracellular free Ca²⁺ concentration has been shown to be elevated in platelets of patients with essential hypertension. This study was designed to characterize Ca²⁺-pump activity of the platelet membranes (surface and intracellular) in these patients. A double-blind study was carried out. Untreated and treated (on R-blockers) essential hypertensives were studied in comparison with normotensive control subjects. First degree blood relatives of essential hypertensives were also studied. The Ca²⁺-activation kinetics of the enzyme showed a significant decrease in the V_max. (for the plasma- and intracellular membranes) and Km (for the intracellular membranes) in the essential hypertensive patients. Increased platelet membrane cholesterol content was observed in these patients. Lowered Ca²⁺-efflux by Ca²⁺-ATPase may lead to elevated intracellular free Ca²⁺-levels in platelets of essential hypertensives. A lowered Ca²⁺-ATPase activity may emerge as a marker for essential hypertension.     

Combined Drug Treatment of Obesity

Pharmacological treatment of obesity has been neglected as a viable therapeutic option for many years. Recent long term studies with combinations of obesity drugs gives promise that drugs may play a role in weight maintenance, which classically has been the most difficult aspect of treating obesity. Currently available obesity drugs include centrally acting adrenergic agents and serotonin agonists. Drugs still in development include a lipase inhibitor that produces fat malabsorption, a combined adrenergic-serotonergic reuptake inhibitor, various gut-central nervous system peptides, and a number of beta-3 agonists. Any of these obesity drugs given alone produces modest weight loss, and for most, weight loss continues for as long as medication is given. The most successful drug regimens to date are combinations of phentermine and fenfluramine or of ephedrine, caffeine, and/or aspirin. The former combination produces reduction in body weight and complications of obesity for 2 to almost 4 years in clinical trials to date. More research is needed to document long term efficacy and particularly the long term safety of these and other combinations.     

Comparisons between the inorganic content of healthy and hypertensive rat tissues by inductively coupled plasma-mass spectrometry

The inorganic contents of bone, brain, erythrocyte, heart, kidney cortex, kidney medulla, liver, lung, muscle and plasma from spontaneously hypertensive rats were compared with those of the same tissues from healthy Sprague-Dawley rats. A general inductively coupled plasma-mass spectrometry method developed for multi-element determinations of most of the elements present in biological tissues was used. Variations were found not only for major elements, as expected, but also for many trace elements in several tissues.     

Tissue distribution of antihypertensive dipeptide, Val-Tyr, after its single oral administration to spontaneously hypertensive rats.

The distribution of an antihypertensive dipeptide, Val-Tyr (VY), in the tissues of spontaneously hypertensive rats (SHR) was investigated in this study. A single oral administration of VY (10 mg/kg) to 18-week-old SHR resulted in a prolonged reduction of systolic blood pressure (SBP) up to 9 h (SBP0h 198.0+/-3.6 mmHg; SBP9h 154.6+/-3.5 mmHg). As a result of VY determination, a roughly 10-fold higher increment of plasma VY level was observed at 1 h than that at 0 h, whereas thereafter the level declined rapidly. In tissues, VY was widely accumulated in the kidney, lung, heart, mesenteric artery and abdominal aorta with the area under the curve over 9 h of more than 40 pmol h/g tissue; of these a higher VY level was observed in the kidney and lung. In addition, a mean resident time (MRT) for each tissue (>5 h except for liver) revealed that VY preferably accumulated in the tissues rather than in the plasma (MRT 3.8 h). Significant reductions of tissue angiotensin I-converting enzyme activity and angiotensin II level were found in the abdominal aorta as well as in the kidney, suggesting that these organs could be a target site associated with the antihypertensive action of VY.