(Hypertension. 1995;26:118-123.)
© 1995 American Heart Association, Inc.
Articles |
Effects of Low and High Doses of Fosinopril on the Structure and Function of Resistance Arteries
From Cattedra di Semeiotica e Metodologia Medica, UOP Scienze Mediche, University of Brescia (Italy).
Correspondence to Prof Enrico Agabiti Rosei, Cattedra di Semeiotica e Metodologia Medica, Scienze Mediche, University of Brescia, c/o 1a Medicina, Spedali Civili, 25100 Brescia, Italy.
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Abstract |
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Abstract It has been suggested that angiotensin-converting enzyme inhibitors may induce a significant regression of cardiovascular hypertrophy not only through blood pressure reduction but also as a possible consequence of growth factor inhibition. The aim of this study was to evaluate the effects of the angiotensin-converting enzyme inhibitor fosinopril, given either at a hypotensive high dose or a nonhypotensive low dose, on structural and functional alterations of mesenteric resistance arteries and on cardiac mass in spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats. Fosinopril was administered in the drinking water from 6 to 12 weeks of age. Rats were killed at 12 weeks, and the ratio of heart weight to body weight was measured. Mesenteric arterioles were dissected and mounted on a micromyograph (Mulvany's technique). Vascular morphology (media-lumen ratio, media thickness) and endothelial function (response to acetylcholine) were then assessed. During the 6 weeks of treatment, systolic pressure in SHR treated with high-dose fosinopril was significantly lower compared with that in untreated SHR, whereas no difference was observed with low-dose fosinopril. In SHR treated with both high-dose and low-dose fosinopril, a statistically significant reduction of vascular structural alterations, in terms of both media-lumen ratio and media thickness, was observed. The ratio of heart weight to body weight was reduced only in SHR treated with high-dose fosinopril. An improvement in the endothelium-dependent relaxation to acetylcholine was observed in SHR treated with high-dose fosinopril compared with untreated SHR, whereas in SHR treated with low-dose fosinopril no improvement in endothelial function was detected. In conclusion, low-dose fosinopril selectively prevented the structural but not functional vascular alterations in SHR, thus suggesting a possible interference of angiotensin-converting enzyme inhibitors with growth factors, at least in the peripheral vasculature.
Key Words: angiotensin-converting enzyme inhibitors • endothelium-derived relaxing factor • vascular resistance • hypertrophy • fosinopril • acetylcholine • rats, inbred SHR • endothelium
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Introduction |
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Structural alterations in the resistance vasculature are almost always associated with hypertension.1 2 3 These abnormalities, which include simple media hypertrophy or remodeling,4 5 may have a significant role in the development and/or maintenance of hypertension because they may amplify the effects of several vasoconstricting agents, including angiotensin II (Ang II) and norepinephrine.6 7 Cell growth is in a large part controlled by peptide and nonpeptide growth factors, among which Ang II seems to play a relevant role8 ; in fact, angiotensin-converting enzyme (ACE) inhibitors exert useful growth regulatory effects.9
Although several drugs have been shown to be effective in reducing cardiac hypertrophy, data regarding a possible regression of vascular structural and functional alterations by antihypertensive therapy are limited. In fact, several ACE inhibitors (captopril, enalapril, cilazapril, perindopril) seem to possess a clear beneficial effect on vascular structure,10 11 12 13 14 15 16 17 18 19 but in all these studies the drugs were given at a hypotensive dose. In one of these studies10 a dose dependency of the effect of the ACE inhibitor perindopril on vascular structure was observed, but none of the doses used were devoid of effects on blood pressure. The results of some experimental studies suggest that ACE inhibitors may induce a significant regression of cardiovascular hypertrophy not only through blood pressure reduction but also as a possible consequence of growth factor inhibition.14 20 21 22
The spontaneously hypertensive rat (SHR) represents an animal model of genetic hypertension in which cardiovascular structural alterations seem to depend at least in part on the activation of the renin-angiotensin-aldosterone system; in addition, enhanced renal Ang II receptor responses have been observed in this strain.23
It has also been observed that ACE inhibitors are able to induce an improvement of endothelial response to acetylcholine and bradykinin in vitro.24 25 In SHR, after long-term therapy with ACE inhibitors19 26 27 or calcium antagonists,27 28 29 endothelial function clearly improved. It is also possible that the beneficial effect of ACE inhibitors on vascular endothelium is not due to the specific mechanism of inhibition of the angiotensin-aldosterone system but to a less-specific hemodynamic effect.
The ACE inhibitor fosinopril is a relatively new compound showing interesting pharmacokinetic and pharmacodynamic properties30 31 with promising and useful clinical effects.32 In particular, fosinopril as well as zofenopril has the highest lipid solubility among the ACE inhibitors currently available33 and could therefore be more effective in penetrating vascular tissue sites and inhibiting actions of the renin-angiotensin system within the walls of arteries and of the heart. Therefore, the aim of the present study was to evaluate the effects of the ACE inhibitor fosinopril, given at either a hypotensive or nonhypotensive dose, on structural alterations and endothelial function of mesenteric resistance arteries as well as on cardiac mass in SHR.
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Methods |
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Ninety-six rats (60 SHR and 36 Wistar-Kyoto rats [WKY]) were included in the study. The rats were obtained from Charles River Laboratory (Calco, Italy). All the procedures followed were in accordance with the guidelines of the Medical School at the University of Brescia.
The rats were housed two to a cage in a temperature-controlled room (between 23° and 25°C) with a 12-hour light/dark cycle. Food and water were supplied ad libitum. Fosinopril was administered in drinking water from 6 to 12 weeks of age at either 1 mg/kg per day (low dose, FOS ld) or 25 mg/kg per day (high dose, FOS hd). Twelve WKY and 20 SHR were treated with FOS ld, 12 WKY and 20 SHR with FOS hd, and 12 WKY and 20 SHR were kept untreated as controls. Rats were killed at the age of 12 weeks. Fig 1 shows the study protocol.
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Systolic blood pressure (SBP) and heart rate were measured noninvasively (tail-cuff method, IITC Life Science Instruments) in conscious rats every week. In our laboratory the average coefficient of variation of the plethysmographic SBP measurement was 5.23% (16 rats, 10 measurements in each rat in a single session).
On the day of death the rats were weighed and then killed by decapitation. The heart was promptly dissected, dried, and weighed, and the ratio of heart weight to body weight (HW/BW) was calculated in all rats; in addition, in both treated and untreated SHR the relative left ventricular mass (RLVM: ratio of left ventricular weight to body weight) was calculated. At the same time, mesenteric vessels corresponding to the second branch (approximately 140 to 200 µm of average diameter in relaxed conditions, 2 mm long) were obtained from each rat by dissection. The vessel segments were excised free of connective and adipose tissue, and two stainless steel wires (40 µm diameter) were threaded through the lumen. This ring preparation was mounted on a micromyograph, as previously described by Mulvany et al.2 Total time for dissection and preparation was approximately 45 minutes. Vessels were then equilibrated and relaxed for at least 30 minutes in physiological saline solution (PSS) with the following composition (mmol/L): NaCl 119, NaHCO3 24, KCl 4.7, KH2PO4 1.18, MgSO4 1.17, CaCl2 2.5, and glucose 5.5, kept constantly at 37°C and bubbled with 5% CO2 in O2.
After equilibration, the micromyograph was transferred to the stage of a light microscope with immersion lens. The vessel was stretched slightly (wall tension approximately 0.1 mN/mm), and structural characteristics of the vessels were evaluated. The following parameters were measured: wall thickness, media thickness, adventitia thickness, intima thickness, internal diameter, media-lumen ratio (M/L), and media cross-sectional area. The normalized internal circumference, L1, then was determined, as described previously by Mulvany et al,2 from the resting wall tension–internal circumference relation and Laplace equation (L1 is defined as 0.9 · L100, where L100 is an estimate of the internal circumference that the vessel would have had in vivo when subjected to a transmural pressure of 100 mm Hg while relaxed). From L1, the normalized internal diameter, l1, was calculated. Assuming that the cross-sectional area remains constant when the vessel is extended to L1, the previously mentioned morphological parameters were automatically calculated also in a normalized condition.
Functional characteristics of the vessels were then evaluated. Vessels were exposed three times to PSS with equimolar exchange of NaCl for KCl (KPSS) (2 minutes, with a 10-minute interval) for evaluation of their response to potassium; the maximal response was usually observed during the third stimulation. A cumulative dose response to acetylcholine was then performed (after precontraction of the vessels with 3x10-6 mol/L norepinephrine) by exposing the vessels to increasing concentrations of acetylcholine, with 2 minutes at each concentration. The response to each concentration was measured as the active force at the end of each 2-minute period. Wall tension (active force divided by two times the segment length) was then calculated. If the vessels produced rhythmic activity, the response was measured from the mean active force for the last 20 seconds of each period. The dose-response curve to acetylcholine was performed at the following concentrations: 10-9, 5x10-9, 10-8, 5x10-8, 10-7, 5x10-7, 10-6, and 10-5 mol/L. The response to acetylcholine was expressed as the percent decrease of the wall tension obtained with norepinephrine precontraction. For further details about the methods used, see References 3 and 283 28 .
All data are expressed as mean±SEM. One-way ANOVA with Bonferroni's correction for multiple comparisons was used when appropriate to evaluate differences among groups. Two-way ANOVA for repeated measures was used for blood pressure and heart rate (groupxtime) as well as for dose-response curves to acetylcholine (groupxdose) (BMDP programs 7D, 1V, and 2V, BMDP Statistical Software Inc).
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Results |
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Blood Pressure
SBP values in untreated and treated SHR and WKY from week 6 to 12 are reported in Fig 2, and SBP values at the time of death are reported in Table 1. At 6 weeks of age, no statistically significant difference in SBP was observed between untreated SHR and WKY. At 12 weeks of age, the SHR treated with FOS hd showed a significant reduction in SBP (-22%), and a small, nonsignificant reduction of SBP was observed during treatment with FOS ld. No difference was observed between treated and untreated WKY; all the WKY groups had SBP values significantly lower than those of the untreated SHR. These results were confirmed by the ANOVA performed during the 6-week period: P<.001, untreated SHR versus SHR treated with FOS hd; P=NS, untreated SHR versus SHR treated with FOS ld; P<.001, untreated SHR versus treated or untreated WKY; and P=NS, treated versus untreated WKY.
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Cardiac Morphology
Values of heart weight, left ventricular weight, body
weight, HW/BW, and RLVM in SHR and WKY are reported in Table 2. HW/BW was significantly increased in untreated SHR
compared with untreated WKY (+12%). A significant reduction of HW/BW
and RLVM was observed in the SHR group treated with FOS hd (-8%) but
not in the SHR group treated with FOS ld. No significant change was
observed in treated WKY. The HW/BW values observed in the SHR treated
with FOS ld as well as with FOS hd are similar to those expected from
the regression between SBP and HW/BW in untreated SHR and WKY (Fig 3).
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), untreated Wistar-Kyoto rats (WKY, 
), SHR treated with
low-dose fosinopril (
), and SHR treated with high-dose fosinopril
(
) (see text).
Vascular Morphology
Values of media thickness, wall thickness, media cross-sectional
area, internal diameter, and M/L in SHR and WKY are reported in Table 3. Untreated SHR clearly showed the presence of vascular
structural alterations. Treatment with both FOS hd and FOS ld induced a
significant reduction of M/L (-18%), media thickness (-25% and
-24%, respectively), and wall thickness (-18% and -16%,
respectively) in SHR. No significant change was observed in treated
WKY.
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The M/L values observed in the SHR treated with FOS hd were similar to those expected from the regression between SBP and M/L in untreated SHR and WKY, whereas in SHR treated with FOS ld the observed M/L was significantly below the value expected (predicted value, 0.123±0.0031; observed value, 0.106±0.0069; P<.05) (Fig 3).
Endothelial Function
No significant difference among the groups (untreated and
treated WKY and SHR) in response to KPSS was observed (Table 4). The response to acetylcholine in untreated SHR was
significantly (P<.001, ANOVA) reduced compared with WKY
(Fig 4, Table 4); no change was observed in SHR treated
with FOS ld, whereas a significant improvement of
endothelial function was observed in SHR treated with
FOS hd (P<.05, ANOVA) (Fig 4, Table 4). No significant
difference in the dose-response curve to acetylcholine between treated
and untreated WKY was observed (Fig 4, Table 4).
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Discussion |
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The results of this study have demonstrated that an ACE inhibitor can clearly reduce structural alterations in small arteries at such a low dose that no statistically significant hemodynamic effects were induced. On the contrary, cardiac structural alterations were reduced only when blood pressure was lowered by the higher dose of fosinopril. Our findings are different from those obtained by Thybo et al10 and Mulvany et al34 in both SHR and Milan hypertensive rats. In those studies perindopril treatment had a dose-dependent effect on blood pressure as well as on structural parameters in different vascular beds; however, none of the doses used were devoid of a hypotensive effect, and therefore the suggestion that without lowering blood pressure no reduction in M/L could be seen may be regarded as an extrapolation.
A partial explanation for these differences may be a possible heterogeneity of the action of different ACE inhibitors, perhaps related to a different dose-dependent penetration in the cardiovascular tissues. Our findings are also partially different from those obtained by Gohlke et al,35 who did not observe any regression of vascular hypertrophy in mesenteric small arteries of SHR with a nonhypotensive dose of the ACE inhibitor zabicipril. These differences could be ascribed to the smaller number of animals used in their study (n=11-14), to the different method of evaluation of vascular morphology, or, again, to a possible heterogeneity of the action of different ACE inhibitors. On the other hand, in that study,35 as well as in our study, a regression of cardiac and vascular hypertrophy was observed with a hypotensive dose of the drug, and no regression of cardiac hypertrophy was observed with a nonhypotensive dose. Baker et al20 and Linz et al21 22 observed a prevention or regression of cardiac hypertrophy with a subhypotensive dose of enalapril or ramipril in Sprague-Dawley rats made hypertensive with aortic banding; this is an animal model of experimental hypertension in which the activation of the renin-angiotensin system is particularly evident. In SHR, the genesis of hypertension and cardiovascular structural alterations is more complex and probably multifactorial. In fact, in a recent study Gohlke et al36 could not observe any reduction in left ventricular mass in stroke-prone SHR when ramipril was given at a low, nonhypotensive dose.
We have previously observed a different time course of cardiac and vascular hypertrophy in young SHR, suggesting a major role of genetic factors in the genesis of vascular abnormalities, which are present before the onset of overt hypertension, and a less-evident influence on cardiac hypertrophy that seems to develop later, when the increased hemodynamic load is an important contributing mechanism.3 Consistent with our finding are the results of Griffin et al,37 who have shown that Ang II infusion is associated with the development of hypertension and cardiac and vascular alterations; but when hydralazine was given with Ang II, hydralazine could prevent the rise of blood pressure and the cardiac effects but not the vascular changes. Moreover, Harrap et al14 previously showed that the reduction of M/L in mesenteric resistance arteries and the prevention of the development of hypertension observed in SHR after treatment with the ACE inhibitor perindopril were abolished by the simultaneous infusion of Ang II at a dose that had only minor direct pressor action in the normal rat.
The administration of an ACE inhibitor in young SHR could influence the developmental characteristics of these animals.14 Therefore, it is possible that the effects of fosinopril on cardiovascular structure in the present study may involve mechanisms beyond the dose used or the extent of blood pressure reduction. However, no difference in body weight between treated and untreated rats and especially between those treated with FOS hd or FOS ld was observed.
The development of high blood pressure in humans and in animal models of genetic or experimental hypertension seems to be associated with an impairment of endothelial function,3 38 39 as evaluated by the vasodilator response to acetylcholine; this abnormality may contribute to the imbalance between vasoconstriction and vasodilatation. Although not all vascular beds are similarly affected,40 in mesenteric resistance arteries an endothelial dysfunction may be clearly observed. The endothelium plays a pivotal role in sensing and transducing the stimuli that induce cell growth and vascular hypertrophy or remodeling41 42 ; therefore, a complex interplay between endothelial dysfunction and vascular structural alterations may be postulated.
ACE inhibitors, either added to the organ bath (perindopril, cilazapril)24 25 or given chronically (cilazapril, benazepril, ramipril),19 26 27 are able to improve the vasodilator response to acetylcholine in small resistance arteries of SHR. It has been speculated that these drugs may improve endothelial function by increasing the release of endothelium-derived growth factor/nitric oxide (EDRF/NO). In one of these studies19 the increase in the vasodilator response to acetylcholine observed after therapy with ramipril was associated with increased aortic cGMP content, suggesting that all the EDRF/NO cascade is activated. However, in that study19 as well as in others26 27 a hypotensive dose of the drugs was used. In our study, no improvement of endothelial function was observed with the low, nonhypotensive dose, thus suggesting a role of blood pressure reduction in the prevention of the development of endothelial dysfunction. Therefore, a clear dissociation between vascular structural alterations and endothelial function was observed. In a previous study we have observed the absence of any endothelial dysfunction in young SHR that showed the presence of vascular hypertrophy.3 The observation of improvement of endothelial function during therapy with calcium channel blockers27 28 29 gives more strength to the hypothesis that a hemodynamic rather than structural factor is involved in both the genesis and prevention or regression of endothelial dysfunction in SHR. Nonetheless, the possibility of additional pharmacological properties of these drugs should be considered.
The improvement of endothelial function in SHR treated with FOS hd was still present after a week of withdrawal of antihypertensive therapy (unpublished data, 1995); therefore, it seems reasonable that the effect on the endothelium-dependent vasodilatation is not due to the possible presence of the drug in the tissue during the experiments.
In conclusion, in SHR, FOS ld selectively prevented structural but not functional vascular changes, thus suggesting a possible interference of ACE inhibitors with growth factors, at least in the peripheral vasculature. Higher doses of fosinopril might have additional important pharmacological properties; in fact, heart weight can be reduced only by the higher dose of fosinopril, and even the prevention of the development of endothelial dysfunction can be observed only in FOS hd–treated SHR. The blood pressure–lowering effect of FOS hd is one but not necessarily the sole explanation of these additional effects on the heart and vascular function.
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Acknowledgments |
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This work was performed under the auspices of the European Working Party on Resistance Artery Disease (EURAD), supported by the European Community under the BIOMED 1 programme. The authors thank Stefano Collatina, MD (Bristol-Myers Squibb SpA, Rome, Italy) for providing fosinopril, and Alessandra Panarotto for her technical assistance.
Received March 7, 1995; first decision April 7, 1995; accepted April 7, 1995.
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D. Rizzoni, E. Porteri, D. Guefi, A. Piccoli, M. Castellano, G. Pasini, M. L. Muiesan, M. J. Mulvany, and E. A. Rosei Cellular Hypertrophy in Subcutaneous Small Arteries of Patients With Renovascular Hypertension Hypertension, April 1, 2000; 35(4): 931 - 935. [Abstract] [Full Text] [PDF]
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 J. Zicha and J. Kunes Ontogenetic Aspects of Hypertension Development: Analysis in the Rat Physiol Rev, October 1, 1999; 79(4): 1227 - 1282. [Abstract] [Full Text] [PDF]
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 D. Rizzoni, M. L. Muiesan, E. Porteri, M. Salvetti, M. Castellano, G. Bettoni, G. Tiberio, S. M. Giulini, C. Monteduro, G. Garavelli, et al. Relations between cardiac and vascular structure in patients with primary and secondary hypertension J. Am. Coll. Cardiol., October 1, 1998; 32(4): 985 - 992. [Abstract] [Full Text] [PDF]
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D. Rizzoni, E. Porteri, A. Piccoli, M. Castellano, G. Bettoni, M. L. Muiesan, G. Pasini, D. Guelfi, M. J. Mulvany, and E. A. Rosei Effects of Losartan and Enalapril on Small Artery Structure in Hypertensive Rats Hypertension, August 1, 1998; 32(2): 305 - 310. [Abstract] [Full Text] [PDF]
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G. Bergstrom, I. Johansson, K. M. Stevenson, M. M. Kett, and W. P. Anderson Perindopril Treatment Affects Both Preglomerular Renal Vascular Lumen Dimensions and In Vivo Responsiveness to Vasoconstrictors in Spontaneously Hypertensive Rats Hypertension, April 1, 1998; 31(4): 1007 - 1013. [Abstract] [Full Text] [PDF]
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D. Rizzoni, E. Porteri, M. Castellano, G. Bettoni, M. L. Muiesan, G. Tiberio, S. M. Giulini, G. Rossi, G. Bernini, and E. Agabiti-Rosei Endothelial Dysfunction in Hypertension Is Independent From the Etiology and From Vascular Structure Hypertension, January 1, 1998; 31(1): 335 - 341. [Abstract] [Full Text] [PDF]
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D. Rizzoni, E. Porteri, M. Castellano, G. Bettoni, M. L. Muiesan, P. Muiesan, S. M. Giulini, and E. Agabiti-Rosei Vascular Hypertrophy and Remodeling in Secondary Hypertension Hypertension, November 1, 1996; 28(5): 785 - 790. [Abstract] [Full Text]
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Y. Dohi, M. Kojima, and K. Sato Benidipine Improves Endothelial Function in Renal Resistance Arteries of Hypertensive Rats Hypertension, July 1, 1996; 28(1): 58 - 63. [Abstract] [Full Text]
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M. Notoya, M. Nakamura, and K. Mizojiri Effects of Lisinopril on the Structure of Renal Arterioles Hypertension, March 1, 1996; 27(3): 364 - 370. [Abstract] [Full Text]
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