Remodeling of the vascular tree in hypertension: drug effects.

The primary aim of current antihypertensive therapy is to lower blood pressure through the reduction of peripheral vascular resistance. Resistance reduction is achieved primarily by interference with acutely acting pressor stimuli. However, recent research has stressed the importance of slow pressor stimuli, which act by gradually remodeling the vascular tree. Long-term remodeling is achieved by a chronic change in vessel number, vascular diameter or wall thickness, involving both physical and chemical factors. The chemical mediators belong to a group of endogenous growth-affecting factors. As Harry Struyker Boudier and colleagues explain in this review, although there are thus far no specific drugs to antagonize the effects of these factors, several therapeutically used antihypertensives influence their action. Moreover, the concept that vascular remodeling is important in hypertension offers exciting new therapeutic targets.

Evaluation of reproducibility of a vessel wall movement detector system for assessment of large artery properties.

OBJECTIVE: Arterial distensibility (DC) and compliance (CC) are vessel wall properties of large arteries that can be measured non-invasively with a custom made vessel wall movement detector system (VWMDS). This study investigated the reproducibility of this device in 10 volunteers. METHODS: To investigate intraobserver intrasession and intraobserver intersession variability, arterial diameter (D) and relative change in diameter during the heart cycle (delta D/D) were measured in the elastic common carotid artery, and in the muscular femoral and brachial arteries. Interobserver intrasession variability was examined in common carotid artery by two observers, while interobserver variability on the same image was assessed for common carotid and femoral arteries. Variability was expressed as the coefficient of variation. RESULTS: For common carotid artery, intraobserver intrasession variability was 7.9(SEM 1.6)% (delta D/D), 4.5(1.1)% (D), 8.3(1.3)% (DC), and 9.1(2.6)% (CC), respectively. In femoral artery it was 12.4(2.2)% (delta D/D), 2.7(0.6)% (DC), 13.4(2.2)% (DC), and 12.5(2.1)% (CC). For brachial artery it was 13.4(2.8)% (delta D/D), 2.5(0.5)% (D), 16.1(2.5)% (DC), and 15.6(2.6)% (CC). Intraobserver intersession variability was comparable to intraobserver intrasession variability for all vessels. Interobserver intrasession variability for common carotid artery was 11.3(2.6)% (delta D/D) and 8.6(1.9)% (D), but was larger for DC and CC. Interobserver variability on the same image was < 5% for common carotid and femoral arteries. CONCLUSIONS: In conclusion, the vessel wall movement detector system has a good technical reproducibility. Intraobserver intrasession and intersession variability are comparable, and are larger in muscular arteries. This might be due to a larger variation in tone of these arteries, which are under permanent neurohumoral control. Interobserver intrasession variability was larger than intraobserver variability and might be influenced by differences in observers' skill and spontaneous variation in vessel wall properties.

Hemodynamic characterization of hypertension induced by chronic intrarenal or intravenous infusion of norepinephrine in conscious rats.

The present study was designed to determine the hemodynamic changes underlying the hypertension induced by chronic intrarenal infusion of norepinephrine (NE) in conscious rats. NE was infused for a 5-day period intrarenally with osmotic minipumps via a chronic catheter in the right suprarenal artery at rates of 4 and 36 micrograms . kg-1 . hr-1 or intravenously at a rate of 36 micrograms . kg-1 . hr-1. Control rats received a 1 microliter . hr-1 intrarenal infusion of pyrogen-free 0.9% NaCl. In separate experiments, short-term effects were measured continuously during a 22- to 24-hour intrarenal infusion of 4 and 36 micrograms NE . kg-1 . hr-1 or intravenous infusion of 36 micrograms NE . kg-1 . hr-1. Intrarenal infusion of NE produced a more pronounced long-term hypertensive effect than infusion of the same dose intravenously. This hypertension was characterized by a rapid and sustained increase in total peripheral resistance index (TPRI). Despite of the initial renal vasoconstriction, specifically produced during the first 24 hours of intrarenal NE application, cardiac index (CI) in parallel to stroke volume index (SVI) decreased significantly during intrarenal as well as during intravenous NE infusion. Furthermore, no signs of sodium retention were observed. Both rates of intrarenal NE infusion have been shown previously to produce a significant long-term increase in plasma potassium concentration, and the present study indicates that this is presumably the result of decreased urinary potassium output. It is concluded that chronic hypertension produced by intrarenal or intravenous infusion is not volume-dependent. The relatively greater increase in TPRI during intrarenal NE infusion is attributed to vascular wall receptor sensitization by increased plasma potassium levels resulting from effects of intrarenally present NE on tubular cation exchange mechanisms.

Microvascular alterations in adult conscious spontaneously hypertensive rats.

The dorsal skin flap technique was used to study skeletal muscle microcirculation in conscious 10-12-week-old spontaneously hypertensive rats and normotensive Wistar-Kyoto control rats. Videorecordings were made for off-line analysis of consecutive segments of the vascular bed. Resting diameters were significantly smaller in spontaneously hypertensive rats than in Wistar-Kyoto rats at the first-order (-28%) and second-order arteriolar (-21%) levels. Precapillary third-order and fourth-order arterioles of spontaneously hypertensive rats had normal diameters, whereas postcapillary small venule diameters were slightly larger in spontaneously hypertensive rats. Thirty percent and 41% of the spontaneously hypertensive rat and Wistar-Kyoto rat third-order arteriolar vessels and 63 and 45% of the fourth-order arteriolar vessels exhibited vasomotion. Vasomotion amplitude, but not frequency, was significantly higher in spontaneously hypertensive rats than in Wistar-Kyoto rats. It is concluded that, in the established phase of spontaneous hypertension in the rat, a decreased diameter of large arterioles is the major mechanism underlying the increased vascular resistance in cutaneous skeletal muscle.

Role of afferent renal nerves in spontaneous hypertension in rats.

In the present study we examined sympathetic function and baroreceptor reflex sensitivity in adult spontaneously hypertensive rats (SHR) after a selective transection of afferent renal nerves in the prehypertensive and established phases of hypertension. Renal deafferentation performed between 3 and 4 weeks after birth did not influence the course of the development of high blood pressure when compared with sham-operated rats. Mean arterial pressure, heart rate, and plasma norepinephrine concentrations were similar in both groups when measured at 13 weeks after renal deafferentation. However, blood pressure responses to ganglionic blockade with hexamethonium were significantly reduced in the renal deafferented SHR. Baroreceptor reflex sensitivity, assessed by heart rate responses to blood pressure changes induced by phenylephrine and nitroprusside, was significantly enhanced in these rats. When renal deafferentation was performed in adult SHR with established hypertension, mean arterial pressure decreased slightly but significantly by 5%. Heart rate, plasma norepinephrine concentrations, and responses to hexamethonium were not affected by this procedure. However, in the renal deafferented adult SHR, heart rate responses to phenylephrine but not to nitroprusside were significantly increased. Thus, in contrast to efferent renal nerves, afferent renal nerves do not play an important role in the development and maintenance of high blood pressure in SHR, but may contribute to the mechanisms that alter sympathetic function and baroreceptor reflex sensitivity in SHR during the development of hypertension.

A functional morphometric study of the cremaster muscle microcirculation in young spontaneously hypertensive rats.

Increased vascular resistance in spontaneous hypertension has been attributed to a reduced arteriolar lumen and a decrease in the number of arterioles and capillaries. In the present study, microvascular mechanisms for increased resistance were investigated in the cremaster muscle of 5-6-week-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY) using intravital microscopy. Vessels were classified on the basis of their location in the network relative to their branching order and function (A1-A4). In each preparation, one vessel of each category was observed for its side-branches, using bright-field microscopy. By comparing the number of side-branches seen under control conditions and after maximal vasodilatation (10(-3) mol/l adenosine, topically) we assessed their functional reserve. Capillary density was investigated using incident fluorescence microscopy. Both under control conditions and after vasodilatation, mean arterial pressure and heart rate were increased in SHR (mean arterial pressure: SHR 103 +/- 4 mmHg, WKY 89 +/- 3 mmHg, P less than 0.05; heart rate: SHR 380 +/- 16 beats/min, WKY 343 +/- 12 beats/min, P less than 0.05). Arterioles (A1-A4) of SHR and WKY were equal in diameter (SHR: 75.8 +/- 3.2, 48.7 +/- 1.1, 21.4 +/- 0.9, 10.0 +/- 0.04 microns; WKY: 71.6 +/- 2.4, 48.9 +/- 1.1, 18.5 +/- 0.9, 9.8 +/- 0.3 microns; A1-A4, respectively). After adenosine, the relative increase in diameter was similar in both groups. The number of side-branches under control conditions was similar in A1 and A2 vessels. SHR had fewer A3 vessels per A2 and fewer A4 vessels per A3 (per unit length), indicating a diminished arteriolar reserve.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of complete renal denervation and selective afferent renal denervation on the hypertension induced by intrarenal norepinephrine infusion in conscious rats.

To test the hypothesis that continuous intrarenal norepinephrine (NE) infusions produce hypertension via activation of afferent renal nerves (ARN), rats were subjected to complete renal denervation (RN-x), selective renal deafferentation (ARN-x) or sham surgery, prior to infusion of NE. In the pre-infusion period, mean arterial pressure (MAP) was significantly lower in RN-x than in ARN-x or sham-operated rats. Plasma renin concentration (PRC) was significantly reduced following ARN-x, but not RN-x. During 5-day intrarenal infusions of 4, 12 or 36 micrograms NE/kg per h, MAP rose to similar levels in RN-x and sham-RN-x rats. However, RN-x rats exhibited significantly elevated PRC levels, suggesting that denervation supersensitivity masked the possible effects of RN-x. In sham-RN-x rats, MAP increased significantly more during intrarenal infusion of 12 micrograms NE/kg per h than during intravenous infusion of the same amount. In ARN-x rats, MAP rose to a similar degree during intravenous and intrarenal infusions. The pressor responses in the ARN-x rats, however, were not significantly smaller at any point than those in intact rats. PRC rose to comparable levels in ARN-x and intact rats. Thus, in normotensive rats, efferent renal nerves (ERN) but not ARN are of functional significance in maintaining basal blood pressure. ARN may be involved in the control of renin release. Since neither RN-x nor ARN-x attenuated the development of hypertension, renal nerves are not necessary for the full expression of hypertension in this model.

The influence of perindopril and the diuretic combination amiloride+hydrochlorothiazide on the vessel wall properties of large arteries in hypertensive patients.

OBJECTIVE: To compare the cardiovascular effects of 6 months of treatment with the angiotensin converting enzyme inhibitor perindopril and with the diuretic combination amiloride+hydrochlorothiazide, and to study possible persistence of observed treatment effects after discontinuation of antihypertensive therapy. DESIGN: A placebo run-in period preceded a 6-month active-treatment phase in 41 patients with essential hypertension, according to a double-blind, randomized, parallel-group design. Patients received either 4 mg perindopril or 2.5/25 mg amiloride+hydrochlorothiazide once a day. Patients were then studied for a 3-month single-blind placebo run-out period. RESULTS: After 6 months of treatment, systolic blood pressure was reduced significantly by perindopril (supine by 11%, sitting by 10%) and by amiloride+hydrochlorothiazide (supine by 8%, sitting by 12%). Diastolic blood pressure was also decreased significantly by perindopril (supine by 8%, sitting by 11%) and by amiloride+hydrochlorothiazide (supine by 4%, sitting by 9%). Mean arterial pressure decreased significantly during treatment with perindopril (by 9%) and with amiloride+hydrochlorothiazide (by 6%). Cardiac index increased with perindopril (by 6%), because of an increased stroke index (by 5%), but amiloride+hydrochlorothiazide did not change cardiac function. Systemic vascular resistance index decreased significantly more with perindopril (by 14%) than with amiloride+hydrochlorothiazide (by 8%). The distensibility of the common carotid artery was significantly enhanced by perindopril (by 16%), but not changed by amiloride+hydrochlorothiazide (1% difference). The difference between perindopril and amiloride+hydrochlorothiazide for carotid distensibility was statistically significant. The compliance of the common carotid artery tended to be increased more by perindopril (by 7%) than by amiloride+hydrochlorothiazide, which induced a 5% decrease in carotid compliance. After withdrawal of therapy, for both drugs, all treatment-induced changes were reversed to pretreatment values within 7 weeks. CONCLUSION: The distensibility of the elastic common carotid artery was increased by perindopril, but not by amiloride+hydrochlorothiazide. Large-artery properties of the muscular arteries and systemic vascular resistance improved with both drugs, but in general the changes were more pronounced with perindopril than with amiloride+hydrochlorothiazide. The present results indicate a more pronounced effect of perindopril at both macro- and microcirculatory levels, which will consequently lead to a larger decrease in cardiac afterload. After discontinuation of therapy all parameters returned to baseline values within 7 weeks.

In vivo DNA synthesis is not uniformly increased in arterial smooth muscle of young spontaneously hypertensive rats.

We compared the distribution of DNA synthesis over the arterial tree of young normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) with marginally elevated blood pressure. Six-week-old male SHR and WKY rats were therefore infused with 5-bromo-2'-deoxyuridine (BrdUrd) for 2 days and the nuclear incorporation of the thymidine analogue in the media of various arteries was determined by immunohistochemistry. In WKY rats, 2.5% of the arterial smooth muscle nuclei in elastic, muscular and resistance arteries incorporated BrdUrd. In SHR, DNA synthesis was more marked in large arteries than in resistance arteries. It was in addition significantly larger in the aorta, superior mesenteric, renal and femoral arteries of the SHR than in those of the WKY rats. However, nuclear incorporation of BrdUrd in vivo did not differ between SHR and WKY rats in aortic endothelium, carotid arterial smooth muscle, nor in mesenteric or renal resistance arteries. Between 6 and 20 weeks of age, the number of nuclear profiles per media cross-section did not increase in large arteries of WKY rats and SHR. During this period of time, however, carotid artery and thoracic aorta weight and DNA content increased. SHR large arteries gained more DNA than those of WKY rats. These data indicate that DNA synthesis is uniformly distributed over the arterial system in young WKY rats and that DNA synthesis is elevated in the smooth muscle of large arteries of 6-week-old SHR but not in their resistance arteries.

Local treatment of renal allografts, a promising way to reduce the dosage of immunosuppressive drugs. Comparison of various ways of administering prednisolone.

A method is described for continuous administration of immunosuppressive drugs directly into rat renal allografts. The drug is given via a catheter, introduced into the suprarenal or testicular artery of the transplanted kidney. The cannula is connected to an implantable osmotic minipump that delivers an immunosuppressive drug with continuous flow for 13 days. It is demonstrated that the technique as such has no detrimental or enhancing effects on renal allograft survival. Depending upon the pharmacokinetic properties of the drug administered, this technique allows a more or less selective treatment of renal allograft rejection. The method was used to test the effect of intrarenal administration of prednisolone on renal allograft survival. Intrarenal administration of this drug appeared to be superior to any other way of administration tested. A low dose of 4 mg/kg body weight per day given by continuous intrarenal infusion results in significant prolongation of graft survival, whereas continuous systemic administration of this dose is not effective. To induce prolongation of graft survival by i.p. administration the prednisolone dose had at least to be doubled. The results prove that during graft rejection local events within the graft are vulnerable to prednisolone. It is concluded that local treatment of allograft rejection is possible and that this approach represents a potentially important way to manipulate the immune response.

Renal selective N-acetyl-L-gamma-glutamyl prodrugs: studies on the selectivity of some model prodrugs.

1. In this study, a number of structurally different N-acetyl-L-gamma-glutamyl prodrugs were investigated with respect to selective uptake by the kidney in male Wistar rats. 2. All prodrugs were tested in vitro in rat kidney slices and kidney homogenate to study their uptake and conversion. It was found that the prodrugs of para-nitroaniline (agPNA), aminophenyl acetic acid (agAFA), sulphamethoxazole (agSM), sulphadimethoxine (agSDM), propranolol (agPP) and metoprolol (agMP) were accumulated by a probenecid-sensitive carrier. The prodrug of 4'-aminoantipyrine (agAAP) was not accumulated by a probenecid- or buthionine sulphoximine-sensitive carrier. Unlike all other prodrugs, agAAP and agMP were not, or only a very limited extent converted to the parent compound in vitro. 3. agPNA, agAFA and agPP were also investigated in vivo. The tissue distribution of the prodrugs and the parent drugs was established, as was their urinary excretion and pharmacokinetic behaviour. agPNA and agAFA showed selective uptake by the kidney, in contrast to agPP which accumulated in the liver. The distribution of the parent compounds following prodrug administration was as follows: agPNA was found in kidney and plasma: agAFA in kidney only; agPP in liver only. 4. The factors which determine the selectivity of N-acetyl-L-gamma-glutamyl prodrugs are discussed. The main factors are: the transport into the kidney, the conversion rate, the residence time of the prodrug in the kidney and the presence or absence of competition for uptake and conversation by other tissues, e.g. the liver. It is concluded that this prodrug approach offers the possibility of delivering drugs selectively to the kidney, but also that it is not universally applicable.

Renal selective N-acetyl-gamma-glutamyl prodrugs: a study on the mechanism of activation of the renal vasodilator prodrug CGP 22979.

1. In this study the processes underlying the renal selectivity of the vasodilator prodrug CGP 22979 (N-acetyl-L-glutamic acid-N-[N2-(5-n-butyl-2-pyridyl) hydrazide]) were studied in rats. 2. The active drug CGP 18137 (2-hydrazino-5-n-butyl pyridine) selectively accumulated in the renal tissue following administration of the prodrug. 3. The kidney concentrations of active drug following prodrug administration were significantly lower than control values when either buthionine sulphoximine, glutathione or probenecid was coadministered (29 +/- 11; 33 +/- 14 and 61 +/- 20% of control values, respectively). Inhibition of gamma-glutamyl transpeptidase by AT-125 did not cause a significant decrease of renal CGP 18137 levels. 4. In order to correlate tissue drug concentrations with pharmacological effect, the renal haemodynamic responses to CGP 22979 were measured and the effect of buthionine sulphoximine, glutathione and AT-125 on these responses evaluated. All three of the compounds attenuated the renal response to the prodrug: an approximately 50% lesser decrease in renal resistance was found. The compounds had no effect on the haemodynamic actions of CGP 18137 itself. 5. In vitro, it was found that kidney cytosol was able to convert the prodrug, whereas microsomes were not, unless acylase was added. 6. The results indicate that, upon prodrug administration, gamma-glutamyl transpeptidase is not involved in the renal accumulation of CGP 18137 but is partly responsible for the renal haemodynamic responses to CGP 22979. Active transport of the prodrug into the tubular cells appears to be the major reason for the renal selectivity. A model is proposed for the renal action of CGP 22979, in which the important parts are the uptake of the prodrug via a transport system followed by an intracellular conversion to the active drug.

Antihypertensive action of beta-adrenoceptor blocking drugs. The role of intrarenal mechanisms.

The different modes of antihypertensive action of beta-adrenoceptor blocking drugs are reviewed with a special emphasis on renal mechanisms of action. Beta-adrenoceptors occur in the kidney at the level of the juxtaglomerular and tubular cells. Direct intrarenal effects of beta-blockers include the decrease in renin release and the enhanced tubular excretion of fluid and electrolytes. Beta-blockers also influence renal function in a more indirect way by altering the activity of different extrarenally formed hormones with an effect on fluid and electrolyte excretion, such as angiotensin II, atrial natriuretic factors and prostaglandins. Several beta-blockers have an additional effect on the renal vasculature. One of these, tertatolol, is a renal vasodilator beta-blocker in different species. The possible mechanisms of renal vasodilatation of tertatolol are reviewed. It is concluded that the shift of the renal pressure-diuresis curve is an essential feature in the mode of long-term antihypertensive action of beta-blockers.

Midbrain central grey: regional haemodynamic control and excitatory amino acidergic mechanisms.

The haemodynamic responses to electrical and chemical stimulation of the periaqueductal or central grey (CG) was investigated in urethane-anaesthetized rats. CG stimulation resulted in a characteristics pattern of mesenteric and renal vasoconstriction accompanied by modest hindquarter vasodilatation. This haemodynamic response was also accompanied by widening of the palpebral fissure, tachycardia and by twitching of the vibrissae. This constellation of physiological responses constitutes the 'defence reaction' and indicates that the CG area under investigation is involved in these phenomena. Both electrical and chemical (kainic acid) lesions of the pressor area of the rostral ventrolateral medulla (RVLM) attenuated the pressor responses to CG stimulation. Intrathecal administration of the excitatory amino acid receptor antagonist kynurenic acid (0.5 mumole/10 microliter) markedly reduced the pressor responses produced by stimulation of both the CG and the RVLM. These results provide additional evidence in support of the notion that neurons arising in the CG relay in the RVLM where they may, in turn, communicate with a descending excitatory amino-acidergic pathway involved in cardiovascular control.

Adrenaline-induced cardiovascular changes after intrahypothalamic administration to rats.

Adrenaline caused a decrease in arterial blood pressure and heart rate when injected into the anterior thalamic region of rats. The size and the duration of these effects depended upon the dose of adrenaline injected. Adrenaline is 10 times more potent than noradrenaline in inducing these intrahypothalamic effects on cardiovascular parameters. These data support the concept of the relevance of adrenaline receptors in central autonomic regulation.

Acute arteriolar vasoconstriction following furosemide in conscious spontaneously hypertensive rats.

In a previous study in conscious spontaneously hypertensive rats (SHR), we observed an immediate decrease in the cardiac index (CI) and an increase in the total peripheral resistance index (TPRI) following the administration of furosemide. The present study was designed to evaluate the regional hemodynamic effects and the involvement of sinoaortic baroreceptors in the increase in TPRI. In SHR instrumented for the measurement of central hemodynamics, 8 mg.kg-1 furosemide decreased CI from 31.0 +/- 2.5 ml.min-1.100 g bw-1 by 9.5 +/- 1.3 ml.min-1.100 g bw-1 (n = 7). TPRI increased maximally from 5.7 +/- 0.8 by 2.7 +/- 0.5 mm Hg.min.100 g bw.ml-1. The effect on TPRI was not affected by sinoaortic denervation (SAD) to abolish arterial baroreflexes. However, furosemide induced a significantly greater decrease in CI (-12.6 +/- 1.2 ml.min-1.100 g bw-1; n = 7) after SAD. Furosemide effectively reduced the mean arterial pressure in SAD SHR (-21 +/- 9 mm Hg) but not in sham-denervated SHR. Furosemide (8 mg.kg-1) reduced renal, mesenteric and hindquarter blood flow to a comparable extent (approximately 20%) in intact SHR. The reduction in renal flow at 3.5 min after injection (-17.9 +/- 4.1%; n = 8) was significantly greater than the reduction in mesenteric (-7.1 +/- 4.7%) and hindquarter blood flow (-4.2 +/- 3.7%), suggesting that the renal bed responds faster. Thereafter, the flow reductions in the three beds were not different. The results show that furosemide causes a general vasoconstriction in conscious SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of the arteriolar vasodilators hydralazine, dihydralazine and endralazine in the conscious spontaneously hypertensive rat.

The hemodynamic effects of the vasodilators hydralazine, dihydralazine and endralazine were studied in conscious, unrestrained spontaneously hypertensive rats (SHR) equipped for chronic hemodynamic measurements. The arteriolar vasodilators hydralazine (0.3 mg/kg i.a.) and dihydralazine (0.3 mg/kg i.a.) caused a rapid fall in blood pressure and peripheral resistance, lasting up to 24 h in the case of dihydralazine. Immediately after injection, the cardiac output and heart rate were increased significantly. These effects only lasted for 1-2 h. The hemodynamic pattern of the new vasodilator endralazine (0.1-1 mg/kg i.a.) was very similar, with a duration of action similar to that of dihydralazine. The role of baroreceptor reflexes in the early hemodynamic effects of vasodilators was studied by comparing the effects of 0.3 mg/kg hydralazine in baroreflex-denervated and non-denervated SHR. The decrease in blood pressure and peripheral resistance was significantly larger in the denervated SHR, whereas increases in cardiac output and heart rate were almost completely absent in these animals. These data suggest that baroreceptor reflexes oppose the early fall in blood pressure and peripheral resistance induced by vasodilators. However, the activity of the baroreflex seems of very short duration, suggesting a rapid adaptation to the prevailing blood pressure. Moreover, the data show that endralazine is an effective arteriolar vasodilator in conscious SHR.

Beneficial hemodynamic effects of two weeks' milrinone treatment in conscious rats with heart failure.

Milrinone is a phosphodiesterase inhibitor which combines vasodilating effects with inotropic effects. Hemodynamic improvement after acute administration and increased survival with chronic milrinone therapy in rats with heart failure have been reported before, and suggest long-term hemodynamic improvement. However, no detailed hemodynamic studies are available on prolonged milrinone therapy in rats with heart failure. Therefore, the hemodynamic effects of 2 weeks' milrinone therapy were now investigated in conscious rats with heart failure due to myocardial infarction. The effects were compared to hemodynamic changes after acute administration. Acute milrinone increased the baseline cardiac output in infarcted rats by increasing heart rate rather than stroke volume. However, the maximal cardiac output achieved when the heart was stimulated through a volume load was improved due to increased stroke volume as well as increased heart rate. The increase in maximally stimulated cardiac output after acute milrinone was found to be related to infarct size. Two weeks' milrinone therapy in chronically infarcted rats dose dependently restored the hemodynamic changes which were caused by infarction. In contrast to acute administration, two weeks' milrinone restored cardiac function without an increase in heart rate. The effects were achieved at a rate of administration which presumably has no acute inotropic effects. The data indicate that acute milrinone in infarcted rats has vasodilating effects. Positive inotropic effects, possibly masked by concomitant venodilatation at baseline conditions, became overt after stimulation by volume loading. Long-term milrinone dose dependently restored cardiac function in infarcted rats without effects on heart rate or mean arterial pressure, suggesting that different mechanisms may be involved.

Microvascular actions of calcium channel antagonists.

The microvascular actions of three calcium channel antagonists were studied in intact spontaneously hypertensive rats (SHR) provided with a dorsal striated muscle microcirculatory chamber. Verapamil and the dihydropyridine derivatives nifedipine and felodipine reduced mean arterial blood pressure (MAP) in a dose-dependent manner. They dilated arterioles of different sizes, with the most pronounced effect being on the smallest precapillary arterioles. Venular diameters were not affected by the calcium antagonists. Approximately 60% of the small arterioles showed a rhythmic pattern of vasodilatation and constriction. This pattern of spontaneous vasomotion was completely blocked by the calcium channel antagonists, especially those of the dihydropyridine type. It is concluded that (a) small precapillary arterioles play an important role in the vasodilator action of calcium channel antagonists, and (b) arteriolar vasomotion depends on vascular smooth muscle cell calcium influx.

Systemic and regional hemodynamic actions of calcium entry blockers in conscious spontaneously hypertensive rats.

In the present study we investigated systemic and regional hemodynamic effects of the calcium entry blockers nifedipine, verapamil and PY 108-068 in conscious SHR. For systemic hemodynamic studies the animals were instrumented with an electromagnetic flowprobe on the ascending aorta, whereas for regional hemodynamic studies miniaturized Doppler flowprobes were implanted on the superior mesenteric and left renal artery and on the abdominal aorta. All three drugs caused a dose-dependent fall in mean arterial pressure and total peripheral resistance. Nifedipine and PY 108-068 increased cardiac output and heart rate, whereas verapamil only did so at high doses. Administration of each calcium entry blocker caused a dose-dependent fall in skeletal muscle vascular resistance, with renal and mesenteric resistance remaining virtually unchanged. A similar effect was observed after the administration of nifedipine to normotensive WKY rats. Surgical elimination of sino-aortic baroreflexes caused a 10 fold increase in antihypertensive potency of the three drugs in SHR. Moreover, dilatation in these animals was uniform in all beds studied. The results indicate that the three calcium entry blockers used are essentially non-selective vasodilators but that baroreflex mechanisms prevent vasodilatation in the renal and mesenteric beds in intact animals.