Relationship between dietary sodium intake, hemodynamics, and cardiac mass in SHR and WKY rats.

To study the effects of sodium intake on circulatory homeostasis and cardiac structure, changes in cardiac mass, systemic hemodynamics, and organ blood flows were determined in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats after 10 wk of controlled dietary intake of low sodium (0.01%), standard sodium (0.44%), and high sodium (2 levels: 1.44 and 4%). Systemic and regional hemodynamics were measured in conscious rats using the radioactive microsphere reference method. The various dietary sodium manipulations did not cause any changes in systemic and regional hemodynamics in the WKY rats. In contrast, the high-sodium diets increased arterial pressure and total peripheral resistance progressively in the SHR rats while decreasing cardiac index, heart rate, and organ blood flows to heart, kidneys, and splanchnic area. The higher sodium intake (4%) increased total and left ventricular mass index in both the SHR and the WKY rats even though hemodynamics of the WKY rats remained unchanged. These data indicate that the high-sodium diet, in addition to producing general vasoconstriction and exacerbation of hypertension, increased cardiac mass further in SHR rats; it also increased cardiac mass in the WKY rats independent of arterial pressure changes, suggesting that high sodium intake may be an independent pathogenetic factor for the development of cardiac hypertrophy.

Quinaprilat increases total body vascular compliance in rats with myocardial infarction.

To test whether quinaprilat, a new angiotensin converting enzyme inhibitor, has any venous effect, its immediate effects were measured on mean circulatory filling pressure (MCFP), intravascular volume and total body vascular (i.e., venous) compliance in conscious rats with mild congestive heart failure induced by coronary artery ligation. MCFP was determined by inflating a right atrial balloon to arrest the circulation instantly and temporarily. Total body vascular compliance was derived from total circulatory pressure-volume relationships as determined by series measurements of MCFP with different intravascular volume status. In 8 rats with mean infarct size of 26 +/- 4%, 30-minute infusion of quinaprilat (0.1 mg/kg/min) decreased both mean arterial and central venous pressures by 8 mmHg and 0.7 mmHg, respectively (P less than 0.02); heart rate, MCFP, hematocrit and blood volume remained unchanged. Compared with control vehicle infusion, quinaprilat increased the total body vascular compliance (2.09 +/- 0.12 vs 2.69 +/- 0.23 ml/kg/mmHg; P less than 0.05) and decreased extrapolated unstressed circulating volume (34.96 +/- 1.10 vs 28.53 +/- 2.55 ml/kg; P less than 0.02). These data suggest that quinaprilat produces possible venodilation through immediately improved total body vascular compliance thereby reducing cardiac preload in this rat model of chronic heart failure.

Quinaprilat increases total body vascular compliance in rats with myocardial infarction.

To test whether quinaprilat, a new angiotensin-converting enzyme (ACE) inhibitor, has any venous effect, we measured its immediate effects on mean circulatory filling pressure (MCFP), intravascular volume, and total body vascular (i.e., venous) compliance in conscious rats with healed myocardial infarction induced by coronary artery ligation. MCFP was determined by inflating a right atrial balloon to arrest the circulation instantly and temporarily. Total body vascular compliance was derived from total circulatory pressure-volume relationships as determined by series measurements of MCFP with different intravascular volume status. In 8 rats with mean infarct size of 26 +/- 4%, 30-min infusion of quinaprilat (0.1 mg/kg/min) decreased both mean arterial and central venous pressures (MAP, CVP) by 8 and 0.7 mm Hg, respectively (p less than 0.02); heart rate (HR), MCFP, hematocrit, and blood volume remained unchanged. As compared with control vehicle infusion, quinaprilat increased total body vascular compliance (2.09 +/- 0.12 vs. 2.69 +/- 0.23 ml/kg/mm Hg; p less than 0.05) and decreased extrapolated unstressed circulating volume (34.96 +/- 1.10 vs. 28.53 +/- 2.55 ml/kg; p less than 0.02). These data suggest that quinaprilat produces possible venodilation through improved total body vascular compliance, thereby reducing cardiac preload in this rat model of myocardial infarction.

ANF does not increase total body venous compliance in conscious rats with myocardial infarction.

To test the hypothesis that atrial natriuretic factor (ANF) increases total body venous compliance through venodilation and thereby reduces cardiac preload, we compared the systemic hemodynamic effects of ANF (99-126) with the venodilator nitroglycerin in conscious rats with myocardial infarction (mean infarct size 25%) induced by coronary artery ligation 3 wk previously. A 30-min ANF infusion (0.5 microgram.kg-1.min-1) decreased mean arterial pressure, central venous pressure, and blood volume by 11 mmHg, 0.8 mmHg, and 3 ml/kg, respectively (P less than 0.02). Nitroglycerin (10 micrograms.kg-1.min-1) similarly reduced arterial and venous pressures (7 and 0.6 mmHg; P less than 0.02) but increased blood volume by 2 ml/kg (P less than 0.05). Both ANF and nitroglycerin reduced mean circulatory filling pressure (MCFP) by 1 mmHg (P less than 0.05). Compared with vehicle infusion, nitroglycerin increased total body vascular compliance as derived from serial MCFP measurements taken during 10% blood volume changes (2.09 +/- 0.12 vs. 2.76 +/- 0.32 ml.kg-1.mmHg-1; P less than 0.05) and reduced extrapolated unstressed volume (34.96 +/- 1.10 vs. 23.79 +/- 3.80 ml/kg; P less than 0.02). In contrast, ANF had no effect on either measurement. These data suggest that ANF and nitroglycerin reduced cardiac filling pressure through different mechanisms; the lack of effects of ANF on total body venous compliance and unstressed volume does not support its venodilating effect in these rats postmyocardial infarction.

Hemodynamic effects of calcitonin gene-related peptide in spontaneously hypertensive rats.

Systemic and regional hemodynamic effects of intravenously injected calcitonin gene-related peptide (CGRP), 220 and 650 pmol, were compared in nine Wistar-Kyoto (WKY) and nine spontaneously hypertensive rats (SHR). CGRP (higher dose) reduced mean arterial pressure (from 135 +/- 2 to 83 +/- 2 and from 179 +/- 4 to 116 +/- 3 mmHg; P less than 0.01, each, in WKY and SHR, respectively) through a fall (-38 +/- 4 and -40 +/- 3%; P less than 0.01) in total peripheral resistance associated with an unchanged cardiac output and an increased heart rate. The decreases in arterial pressure and total peripheral resistance were not different between these two strains. Of particular significance were the highly selective reductions in organ vascular resistances, being greatest in the cutaneous (-78 +/- 3 and -67 +/- 4%) and gastric (-80 +/- 3 and -84 +/- 2%) circulations in WKY and SHR, respectively (P less than 0.01). Reduction in coronary, cerebral, and hepatic vascular resistances, although significant (P less than 0.05, at least), were only moderately reduced compared with the two former circulations. These effects were similar in WKY and SHR and demonstrate that CGRP is a highly selective and potent natural vasodilating peptide that has the most striking effects in skin and stomach, suggesting possible modulator functions in regulating certain regional hemodynamics.

Uptake of catamphiphilic drugs into erythrocytes and muscular tissue correlates to membrane enrichment and to 45Ca displacement from phosphatidylserine monolayers.

The uptake of the catamphiphilic drugs flunarizine, R 56865 [N-1-4-(4-fluorophenoxy)butyl-4-piperidinyl-N-methyl-2- benzothiazolamine], verapamil, diltiazem, lidocaine and the noncatamphiphilic drug nitrendipine into erythrocytes and erythrocyte membranes was measured at pH 7.2 in a Ringer's solution at 22 degrees C. The uptake was concentration proportional between 10(-8) and 10(-6) mol/l for all drugs investigated; the erythrocyte/medium ratio (E/M) was constant after 20 min in all experiments. In rat aortas and left atria drug uptake was measured in a 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffered medium (pH 7.2, 32 degrees C). Equilibrium was reached after 360 min and the tissue/medium ratio (T/M) was concentration proportional between 10(-8) and 10(-6) mol/l for all drugs. E/M or T/M ratios, respectively, increased in the order: erythrocytes less than aortas less than left atria. However, the particular drug/phospholipid ratios were relatively constant for the drugs investigated, indicating that the membranes were a major distribution phase for these drugs. For the catamphiphilic drugs, the E/M or T/M ratios correlated linearly with the EC50 for 45Ca displacement from phosphatidylserine monolayers, but were poorly correlated with the octanol-water coefficient of the unchanged molecules. The EC50 for 45Ca displacement from phosphatidylserine monolayers is a measure for the uptake of the protonated species of catamphiphilic drugs into erythrocytes or tissue and may be a good estimate of tissue uptake of these drugs in general.

Ventricular performance in spontaneously hypertensive rats (SHR) with reduced cardiac mass.

This study was designed to investigate the effect of 4 weeks of captopril treatment on cardiac mass and performance in spontaneously hypertensive rats (SHR). Left (LV) and right (RV) ventricular mass of SHR and normotensive WKY rats was reduced (p less than 0.01). Mean arterial pressure (MAP) and total peripheral resistance index (TPRI) in the treated SHR and WKY were reduced; cardiac (CI) and stroke (SI) indices remained unaltered in SHR but increased in WKY. Ventricular performance (i.e., cardiac pumping ability), assessed by rapid blood infusion, did not differ between untreated SHR and WKY, and between treated and untreated WKY rats. However, the ventricular performance curves for the treated SHR shifted down and to the right from the untreated SHR (p less than 0.01). Moreover, when MAP of treated SHR (with regressed LV mass) was elevated to their pretreatment levels, cardiac performance curves shifted further rightward and downward. In contrast, the performance curves of treated WKY whose MAP was also elevated to the level of untreated WKY were no different from those of untreated WKY. These data demonstrate that captopril treatment (at doses used in this study) reduced MAP in SHR through decreased TPRI while decreasing biventricular mass. Furthermore, the cardiac-pumping ability of previously hypertrophied SHR hearts was reduced, suggesting that certain antihypertensive agents that diminish cardiac mass could produce impaired cardiac function when called upon to increase performance (e.g., when MAP is suddenly raised).

Immediate and prolonged hemodynamic effects of TA-3090 on spontaneously hypertensive (SHR) and normal Wistar-Kyoto (WKY) rats.

Systemic and regional hemodynamic effects of the new effects of the new calcium antagonist TA-3090, a benzothiazepine derivative that is similar to diltiazem, were studied both acutely (0.3 and 0.6 mg/kg IV) and chronically (30 mg/kg by once-daily gastric gavage for 3 weeks) in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. All hemodynamic data were obtained in the conscious state using the reference sample radiomicrospheres method. Mean arterial pressure was reduced significantly by both immediate and long-term treatment in both rat strains. Stroke index remained unchanged in each study group, but the heart rate of the SHR and WKY decreased and increased, respectively, with the higher dose in the intravenous aspect of this study. As a result, total peripheral resistance decreased significantly in all groups, normotensive or hypertensive, although this fall was not distributed uniformly throughout the body. Intrarenal hemodynamics revealed significant differences between SHR and WKY by prolonged treatment with TA-3090. Efferent as well as afferent glomerular arteriolar resistances decreased and therefore calculated glomerular capillary hydrostatic pressure decreased in SHR; however, efferent glomerular arteriolar resistance and glomerular pressure remained unchanged in WKY. By contrast, in the acute study, no such differences were obtained. Further, 3 weeks' treatment did not alter cardiac mass in either rat strain. Thus, TA-3090 decreased arterial pressure through a fall in total peripheral resistance without major cardiac effects in both rats strains. In contrast, the agent reduced vascular resistances only in the SHR; and this was achieved with dilation of both the afferent and efferent glomerular arterioles.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic comparison of diltiazem and TA-3090 in spontaneously hypertensive and normal Wistar-Kyoto rats.

Systemic and regional hemodynamic effects of 2 benzothiazepine derivatives, diltiazem and its congener TA-3090, were studied both acutely and chronically in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. All hemodynamic data were obtained in the conscious state using the reference sample radiomicrosphere method. Mean arterial pressure was reduced significantly with both immediate and more long-term treatment with both drugs in the SHR. The hypotensive action of TA-3090 was about 3 times as potent as diltiazem. The pressure reduction with both drugs was associated with a decrease in total peripheral resistance. TA-3090 seemed to have lesser effect on heart rate than diltiazem, although its net effect on cardiac output was similar, remaining unchanged in each study group. After intravenous injection, both diltiazem and TA-3090 significantly reduced vascular resistances of the major target organs of hypertension: heart, brain and kidneys in SHR. However, with prolonged treatment, organ vascular resistances seemed to be nonuniformly distributed. Intrarenal hemodynamics revealed significant differences between SHR and WKY rats after intravenous diltiazem and prolonged treatment with TA-3090. Thus, efferent as well as afferent arteriolar resistance decreased and therefore calculated glomerular capillary hydrostatic pressure decreased in SHR; however, efferent resistance and glomerular pressure remained unchanged in WKY rats. In contrast, intravenous TA-3090 evoked no such differences. Thus, diltiazem as well as TA-3090 dilated efferent as well as afferent arterioles in the SHR but not in the WKY rats. This effect was associated with a reduction in glomerular capillary pressure, preventing glomerular hyperfiltration through efferent arteriolar dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of slowly exchanging 45Ca in rat aorta without using EGTA or lanthanum and its application to quantify the effects of the calcium entry blockers nifedipine and verapamil.

In rat aortic strips a method was developed to measure a fraction of slowly exchanging 45Ca, which correlates with contraction and the cytosolic Ca pool that is enhanced by K+-induced depolarization. In this method no EGTA or lanthanum are used, but the strips are washed for 45 min with a Tyrode solution at 4 degrees C. The K+ depolarization induced increase in 45Ca and contraction was concentration-dependently inhibited by verapamil and nifedipine. Since lanthanum and EGTA affect cellular membranes, this method may allow a more physiological approach to the measurements of slowly exchanging 45Ca.

Diltiazem maintains renal vasodilation without hyperfiltration in hypertension: studies in essential hypertension man and the spontaneously hypertensive rat.

The systemic and renal hemodynamic effects of diltiazem were determined in patients with mild to moderately severe essential hypertension and in rats with spontaneous hypertension (SHR). Seven patients were treated for one full year (300 mg/day, average dose) and 10 SHR and 10 normotensive Wistar-Kyoto (WKY) rats received 1 and 2 mg/kg, intravenously. In both man and rat with genetic hypertension, arterial pressure was reduced through a fall in total peripheral resistance without associated reflexive increases in heart rate and cardiac index; and the patients demonstrated no change in plasma volume. In both man and the SHR: renal blood flow increased (in SHR not statistically significant) as arterial pressure and renal vascular resistance fell; glomerular filtration rate (GFR) remained unchanged and the filtration fraction (FF) significantly fell; and calculated intrarenal hemodynamic indices (using the Gomez formulae) demonstrated falls in afferent and efferent glomerular arteriolar pressures and resistances and in intraglomerular pressures, thereby explaining the unchanged GFRs and the decline in FF. These findings in both hypertensive man and rat are in contrast with those of the normotensive WKY that only demonstrated a fall in afferent glomerular arteriolar resistance. Thus, these data demonstrate that diltiazem controlled arterial pressure in both forms of genetic hypertension associated with falls in systemic and renal arteriolar resistances and with improved intrarenal hemodynamics without glomerular hyperfiltration.

Vasorelaxant and natriuretic activities of synthetic atrial peptides.

The vasorelaxant and natriuretic activities of synthetic atrial natriuretic peptides (ANF) were compared by measuring relaxation of histamine-contracted rabbit aortic rings and changes in urinary sodium excretion in anesthetized rats. The peptides studied and their relation to pro-ANF were: atriopeptins (AP) I, II and III (ANF 103-123, 103-125, 103-126), cardionatrin (CN) (ANF 99-126), alpha-human atrial natriuretic polypeptide (alpha-hANP) (human 99-126) and a fragment of the last (hFrag) (human ANF 105-126). The concentration causing 50% relaxation (EC50) in the vasorelaxant assay for API was greater than that of the other peptides (p less than 0.05). The EC50 for hFrag was 20 times greater than that of alpha-hANP, but this difference was not statistically significant. API caused less natriuresis compared with the other peptides (p less than 0.05). The natriuresis induced by CN was significantly greater than that of the other peptides at the 485 pmol dose. These results indicated that, except for API, the peptides studied has similar vasorelaxant and natriuretic activities.

Enhanced erythropoietin production by calcium entry blockers in rats exposed to hypoxia.

In order to determine the influence of calcium on erythropoietin release in response to hypoxia, the effects of the calcium entry blocker verapamil on erythropoietin production were investigated. Hypoxia was induced in male Sprague-Dawley rats by placing them in a hypobaric chamber at 0.42 atmospheres for 6 and 12 hr. Serum levels of erythropoietin were measured by the exhypoxic polycythemic mouse bioassay and a sensitive radioimmunoassay for erythropoietin. Verapamil (5, 10 and 20 mg/kg i.p.) produced significant increases in mean serum erythropoietin levels after 6 and 12 hr of hypoxia, which was significantly higher than those of saline-injected hypoxic control rats. Mean arterial blood pressure values in rats injected with 5 and 10 mg/kg of verapamil were not significantly different from the preinjection controls when measured at ambient pressure over a 12-hr period. A dosage of 20 mg/kg of verapamil i.p. in rats produced a significant decrease in mean arterial pressure between 5 and 30 min after injection but was not significantly different from the vehicle controls between 30 min and 12 hr postinjection. In conclusion, the calcium entry blocker verapamil enhanced erythropoietin production in response to hypoxia. Thus, it is postulated that calcium plays a significant role in erythropoietin production and/or release.

Hemodynamic effects of atrial natriuretic hormone.

The atrial natriuretic hormone (ANH) alters cardiovascular function independent of changes in body fluid volume. Most investigators agree that ANH decreases mean arterial pressure (MAP). However, although some investigators have observed a decrease in total peripheral resistance in association with the decrease in MAP, a more frequent observation has been decreased cardiac output (CO). The mechanism whereby ANH decreases CO is unknown, but does not appear to be the result of direct myocardial depression, reductions in intravascular or cardiopulmonary volumes, or venodilation. Alterations in skeletal muscle and splanchnic blood flow have been reported by some but not all investigators. Although increases in renal blood flow have been reported, they are transitory and have not been consistently observed by all researchers. The cardiovascular effects of ANH appear to be influenced not only by the dose, but also by the cardiovascular control mechanisms that operate at the time of ANH administration. Non-renin-dependent hypertensive models exhibit a decrease in MAP associated with decreased CO, whereas in renin-dependent animals this hypotension is associated with a decrease in total peripheral resistance.

Atriopeptin III does not alter cardiac performance in rats.

The effects of atriopeptin III (APIII) on systemic haemodynamics were examined in 12 anaesthetized rats. Five minutes following intravenous injection (i.v.) of 10 micrograms/kg APIII, cardiac output CO, measured by electromagnetic flowmetry, stroke volume and mean arterial pressure (MAP) decreased by 14, 13 and 8% (P less than 0.05), respectively, and total peripheral resistance (TPR) increased by 10% (P less than 0.05). Heart rate (HR) and left ventricular end-diastolic pressure (LVEDP) did not change. In order to examine cardiac performance, whole blood was infused into three groups of 12 rats each receiving either no injection, APIII (10 micrograms/kg i.v.) or APIII (10 micrograms/kg i.v.) plus a continuous infusion of phenylephrine to increase MAP to pre-injection levels. Cardiac performance curves did not differ among the three groups. These data indicate that the immediate decreases in MAP and CO produced in rats by a maximum natriuretic bolus dose of APIII were not mediated by a negative myocardial inotropic effect.

Dehydration attenuates the acute natriuretic response to rat atriopeptin III (rAPIII).

The acute natriuretic response to atrial peptides (AP) is highly variable in anesthetized rats, and some rats are unresponsive. To determine if this response to AP was affected by dehydration, we measured hematocrit, plasma volume, and natriuresis (delta UNaV) after intravenous injection of 3 micrograms/kg of rat atriopeptin III (rAPIII) in anesthetized rats deprived of water for 0, 12, 20, 29, 44, and 68 hours. Data were compared with those from rats receiving 1.5 mg/kg furosemide (FU) after 0 and 68 hours without water. There were 10- and 3-fold decreases in delta UNaV following rAPIII and FU injection after 20 and 68 hours without water, respectively. Hematocrit increased and plasma and total blood volumes decreased after 12 hours of dehydration. Plasma volumes and delta UNaV were correlated (r = 0.64, p less than 0.05; r = 0.75, p less than 0.001) in the combined groups receiving rAPIII (n = 30) and FU (n = 10), respectively. These results demonstrate that a relatively short period of water deprivation (WD) and the resulting hemoconcentration in rats decreased their acute natriuretic response to diuretics. Thus, differences in water intake may account for some of the large variation in delta UNaV after exogenous administration of rAPIII.

The effect of prolonged administration of CGS 10078B on systemic and regional haemodynamics in normotensive and spontaneously hypertensive rats.

The effects of 3 weeks treatment with CGS 10078B (30 mg/kg orally) on systemic and regional haemodynamics and cardiac mass were studied in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. The significant decrease in mean arterial pressure (MAP) (174 +/- 3 versus 156 +/- 4 mmHg, P less than 0.002) in SHR was associated with a significantly slower heart rate. No significant alteration in systemic haemodynamics was observed in WKY rats. The reduced MAP in SHR was related to the preserved blood flow to the vital organs, and therefore reduced renal and cerebrovascular resistances. Left ventricular mass index was reduced in both rat strains of treated animals. Therefore, the reduced MAP and heart rate in the SHR without haemodynamic changes in the WKY indicates that CGS 10078B was an effective antihypertensive agent that decreased cardiac mass in rats through mechanisms that may be dissociated from their haemodynamic effects.

Acute haemodynamic effects of the atrial natriuretic hormone in rats.

Haemodynamic effects of atriopeptin II (AP II) were determined in conscious and anaesthetized rats chronically instrumented with a Doppler flow probe on the ascending aorta. Intravenous injection of AP II (7 micrograms/kg) produced a decrease in mean arterial pressure within 5 min; however, a biphasic change occurred in total peripheral resistance (TPR). At 1 min in the anaesthetized rats, TPR decreased while cardiac output tended to increase, and similar changes occurred in the conscious rats. By 5-8 min the haemodynamic profile had reversed: cardiac output had decreased in both anaesthetized and conscious rats and TPR had increased in anaesthetized rats. Mean circulatory filling pressure (MCFP) was measured during brief circulatory arrest by inflating an intracardiac balloon. Blood volume was measured with 51Cr-erythrocytes and organ blood volume by whole-animal freezing in liquid nitrogen. There were no changes in MCFP in the conscious and the anaesthetized rats, nor in the blood volume or cardiopulmonary blood volume in the anaesthetized rats, at 5-7 min after AP II. Atriopeptin III (10 micrograms/kg intravenously) had no effects on MCFP and the blood volume in the conscious rats at 5 and 15 min after injection. These results suggest multiple mechanisms of action for the acute haemodynamic effects of atrial peptides.