Ben G. Zimmerman

Kinin contribution to renal vasodilator effect of captopril in rabbit.

This study was conducted to examine the role of bradykinin in the persistence of the renal vasodilator effect of captopril during angiotensin II receptor blockade. Blood pressure and renal blood flow were monitored in eight groups of pentobarbital-anesthetized rabbits. In group 4, captopril alone was administered, and it decreased blood pressure by 14 ±4 mm Hg and increased renal blood flow by 21 ±4 ml/min. After a bolus injection and a constant intravenous infusion of the imidazole derivative angiotensin II receptor antagonist DuP 753 (group 5), captopril decreased blood pressure by 9±2 mm Hg and increased renal blood flow by 8±1 ml/min (12±1% change in renal blood flow, p<0.05 versus group 4). In the presence of a constant intravenous infusion of saralasin (group 6), captopril decreased blood pressure by 13±5 mm Hg and increased renal blood flow by 7±2 ml/min (17±5% change in renal blood flow, /?<0.05 versus group 4). These results did not differ from those in group 5. During a constant intrarenal arterial infusion of a B2 bradykinin receptor antagonist, DArg°,[Hyp3- Thi^-nPhe7]-bradykinin (BkA) (group 7), captopril decreased blood pressure by 14±4 mm Hg and increased renal blood flow by 10±4 ml/min. Combined administration of DuP 753 intravenously and BkA intra-arterially (group 8) eliminated the effect of captopril. In group 8, captopril caused insignificant changes in blood pressure and renal blood flow. The results indicate that DuP 753 and saralasin antagonize the renin-angiotensin system to a comparable extent in vivo. Although blockade of the latter system accounted for a significant part of the increase in renal blood flow caused by captopril, the remaining component was contributed by endogenous bradykinin.

Bradykinin contribution to renal blood flow effect of angiotensin converting enzyme inhibitor in the conscious sodium-restricted dog.

We examined the relative contribution of renin-angiotensin system blockade and bradykinin potentiation to the renal hemodynamic effect of the angiotensin converting enzyme inhibitor enalaprilat in sodium-deprived dogs. Six conscious dogs instrumented for monitoring of blood pressure (BP) and renal blood flow (RBF) were employed in five groups of experiments. In group 1, enalaprilat alone was administered, and it decreased BP by -24 +/- 3 mm Hg and increased RBF by 135 +/- 15 ml/min. During a constant intravenous infusion of saralasin (group 2), enalaprilat decreased BP by -7 +/- 3 mm Hg and increased RBF by 84 +/- 7 ml/min (delta BP and delta RBF, p less than 0.01 vs. group 1 by analysis of variance). During a constant intrarenal arterial infusion of saralasin (group 3), the respective changes in BP and RBF after enalaprilat were -10 +/- 3 mm Hg and 69 +/- 12 ml/min, and these results did not differ from those of group 2. The infusion of saralasin intravenously or intrarenal arterially decreased BP slightly and increased RBF. In the presence of an intravenous infusion of a specific bradykinin antagonist, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg.TFA (B5630) (group 4), enalaprilat decreased BP by -28 +/- 4 mm Hg and increased RBF by 82 +/- 24 ml/min (delta RBF, p less than 0.01 vs. group 1).(ABSTRACT TRUNCATED AT 250 WORDS)

Postsynaptic α1- and α2-Adrenergic Mechanisms in Coronary Vasoconstriction

Summary: This study examined the relative importance of postsynaptic α1- and α2-adrenoceptors in mediating coronary vasoconstriction in open chest dogs in which the left circumflex coronary artery was cannulated and perfused at a constant rate. The cervical vagus nerves and central connections of the stellate ganglia were transsected, and β-adrenergic blockade was produced with propranolol. Coronary vasoconstriction occurred in response to intraarterial administration of both the α1-agonist phenylephrine and the α2-agonist BHT 933. The response to phenylephrine was partially blocked with prazosin and nearly completely eliminated by yohimbine. The response to BHT 933 was resistant to prazosin, but almost completely blocked by yohimbine. Coronary vasoconstriction produced by norepinephrine was resistant to prazosin, but was blunted by α2-adrenergic blockade with yohimbine or idazoxan. Prazosin produced some blunting of coronary vasoconstriction in response to small doses of epinephrine, while yohimbine markedly attenuated epinephrine-induced vasoconstriction at all doses used. Measurements of regional myocardial blood flow with radioactive microspheres demonstrated no transmural redistribution of perfusion during vasoconstriction produced by either α1- or α2 stimulation. Thus, although stimulation of both α1- and α2-adrenoceptors is capable of causing coronary vasoconstriction, vasoconstriction in response to norepinephrine and epinephrine is mediated principally by postsynaptic α2-adrenoceptors.

Renal vasodilatation caused by captopril in conscious normotensive and Goldblatt hypertensive dogs.

Abstract Blood pressure and renal blood flow were monitored in conscious normotensive and two-kidney one-clip Goldblatt hypertensive dogs. Captopril administered IV in a single dose of 0.1 mg/kg to normotensives increased renal blood flow by 26.8 ± 7.6% and decreased renal vascular resistance, but did not significantly change blood pressure. Cumulative doses of 0.1 and 0.2 mg/kg increased renal blood flow by 29.9± 6.5%, and decreased renal vascular resistance and blood pressure significantly. Qualitatively similar changes in blood flow and vascular resistance of the contralateral kidney were obtained in the hypertensives. Blood pressure was reduced by a mean of 11.8 ± 4.5 mm Hg, renal blood flow increased by 36.2 ± 7.9% by the low dose, blood pressure decreased by 18.4 ± 2.7 mm Hg, and renal blood flow increased by 42.3 ± 11.4% by cumulative doses of the inhibitor. Plasma renin activity was increased by captopril in the normotensives and a greater increase in plasma renin activity was obtained in the hypertensives. The hypotensive and renal vasodilator effects of captopril appear to be related to blockade of the influence of the renin-angiotensin system, but another action, potentiation of kinin-induced vasodilatation, may also be involved.

Peripheral circulation in arterial hypertension

The underlying causes of hypertensive disease remain unclear. This article has attempted to highlight potential dysfunctions in arterial pressure regulation which could either initiate or sustain the hypertensive process. As has been suggested innumerable times hypertension must certainly be a multifactorial abnormality. The current state of knowledge about control of the peripheral circulation in high arterial pressure reinforces the view that interactions between neurogenic, myogenic, humoral, and structural factors are probably disrupted when hypertension appears.

Kinin-Mediated Antihypertensive Effect of Captopril in Deoxycorticosterone Acetate–Salt Hypertension

On the basis of evidence suggesting the activation of the kallikrein-kinin system in steroid-induced hypertension, we considered the possibility that the angiotensin-converting enzyme inhibitor captopril would lower the arterial blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertensive rats through kininase II inhibition. In conscious DOCA-salt hypertensive rats with intact kidneys (n = 6) or uninephrectomized rats (n = 5), the short-term administration of captopril (8 mg/kg IV) decreased mean blood pressure from 141 +/- 3 to 118 +/- 3 mm Hg (P < .05) and from 176 +/- 12 to 158 +/- 15 mm Hg (P < .05), respectively. The maximal effect of captopril was manifested between 40 and 50 minutes after its administration, and blood pressure remained depressed for at least 2 hours. The bradykinin B2 receptor antagonist Hoe 140 (500 micrograms/kg IV) abolished the antihypertensive effect of captopril in the DOCA-salt hypertensive rats, indicating kinin involvement. Losartan, an angiotensin type 1 receptor antagonist, had no effect on blood pressure in another group of DOCA-salt hypertensive rats (n = 9) and did not significantly change the response to captopril. No effect of the angiotensin-converting enzyme inhibitor was seen in normotensive control rats (n = 5), indicating the absence of a nonspecific hypotensive action of the drug. Plasma renin activity was lower in the DOCA-salt hypertensive rats (0.7 +/- 0.2 ng angiotensin I/mL per hour, n = 4) than in normotensive control rats (8.8 +/- 1.7, n = 4). The involvement of kinins in the antihypertensive effect of captopril in DOCA-salt hypertension supports the contention that the kallikrein-kinin system contributes to blood pressure regulation in this hypertension model.

Angiotensin II-mediated renal vasoconstriction amenable to α1-adrenoceptor blockade

Abstract Renal adrenergic interactions of intravenously and intrarenal arterially administered angiotensin II were studied in the anesthetized rabbit. Systemic arterial blood pressure and left renal blood flow were monitored. Bolus doses of angiotensin II, 50 and 100 ng/kg given intravenously, caused an immediate reduction in renal blood flow followed by a more sustained vasoconstrictor response. Prazosin, 5 μg/kg/min, infused intrarenal arterially, decreased both components of the reduced renal blood flow, suggesting adrenergic contribution to the response. Renal denervation reduced significantly the immediate response to angiotensin II without affecting the sustained response; administration of prazosin after denervation caused a further decrease in the response. Left adrenalectomy had no significant effect on the angiotensin II-induced renal blood flow response, ruling out the possible contribution of adrenal catecholamine release via the adrenal rete. In animals that had undergone renal denervation and left adrenalectomy, the renal blood flow response to intrarenal arterial injection of subpressor doses of angiotensin II (5 and 10 ng/kg) was reduced by the infusion of prazosin. It is concluded that angiotensin II-induced renal vasoconstriction is contributed to by adrenergic actions dependent in part on intact renal nerves, but also by a component not requiring an intact nerve supply.

Characterization of intrarenal arterial adrenergic receptors in renovascular hypertension.

α-Adrenergic receptor subtypes were investigated using [3H]prazosin, an α1 selective antagonist, and the α2 selective antagonist [3H]rauwolscine in a smooth muscle plasma membrane enriched microsomal fraction prepared from rabbit intrarenal arterial vasculature. Both radioligands displayed single components on Scatchard analysis. The specific binding of [3H]prazosin was of high affinity (0.54±0.04 nM) with a maximum binding capacity (Bmax) of 212±15 fmol/mg protein. The maximum number of [3H]rauwolscine binding sites was 64±4 fmol/mg of protein with a dissociation constant (Kd) of 5.60±0.27 nM. Binding of both radioligands was rapid, saturable, and specific, α1- and α2-adrenergic receptors in the intrarenal arterial membrane preparation were also characterized at 2-, 4-6-, and 10–12-week intervals during the course of development and maintenance of chronic two-kidney, one clip (2K1C) Goldblatt hypertension and in age-matched sham-operated normotensive control rabbits. The α1-adrenergic receptor affinity for [3H]prazosin binding in hypertensive rabbits was significantly increased in the stenotic, but not contralateral, kidney at 2 weeks; however, at 6 weeks the receptor affinity of both kidneys was significantly increased compared with those of the normotensive control group. No difference in α1-adrenergic receptor affinity was seen at 12 weeks, and there were no changes in Bmax at any of the weekly intervals. Neither the Kd, nor Bmax, for [3H]rauwolscine in either kidney showed a significant difference between hypertensive rabbits and normotensive control rabbits. These studies demonstrate the existence in the rabbit intrarenal arterial vasculature of binding sites with α1- and α2-adrenergic receptor specificity. Further, intrarenal arterial α1-adrenergic receptor affinity is significantly increased early (to at least 6 weeks) but not later (at most 12 weeks) during 2K1C Goldblatt hypertension.

Nitric oxide participation in renal hemodynamic effect of angiotensin converting enzyme inhibitor lisinopril

Nitric oxide (NO) contribution to the renal hemodynamic effect of lisinopril was assessed in anesthetized rabbits. NG-Nitro-L-arginine (NArg), slightly decreased renal blood flow following vehicle. Also, NArg reversed partially the increase in renal blood flow caused by DuP 753, and almost completely reversed the effect of lisinopril. The results suggest that NO plays an important role in the renal hemodynamic effect of lisinopril, more so than its contribution to the effect of DuP 753.

Beta-adrenergic-induced local angiotensin generation in the rabbit hind limb is dependent on the kidney.

Evidence was sought for β-adrenergic-induced increase in femoral vascular angiotensin production in sham-operated and nephrectomized rabbits. Systemic blood pressure and right femoral blood flow were monitored in anesthetized rabbits. Arterial and femoral venous plasma angiotensin II (Ang II) and angiotensin I (Ang I) were measured by radioimmunoassay after high-performance liquid chromatography. Isoproterenol, 1 and 10 nmol/min, was infused intrafemoral arterialiy, reducing femoral vascular resistance by 47±;5% and 60±6% in the sham-operated group, and by 50±6% and 63±4% in the nephrectomized group, respectively. The hemodynamic effect of isoproterenol was blocked by 2 μmol/kg propranolol injected intravenously plus 0.2μmol/min infused intrafemoral arterialiy, indicating that the effect was β-adrenergically mediated. In the sham-operated group, arterial Ang II and Ang I levels were increased, respectively, by 85±16% and 103±23% with the low dose of isoproterenol, and by 121±13% and 563±126% with the high dose of isoproterenol. The apparent femoral Ang II secretion rate was increased by 3.2-fold and 4.4-fold, and the apparent femoral Ang I secretion rate increased by 4.3-fold and 21.2-fold, with the low and high dose of isoproterenol, respectively. Propranolol abolished or markedly attenuated the increased arterial angiotensin levels and the increased femoral angiotensin secretion rates. Neither the low nor the high dose of isoproterenol caused any increase in plasma levels or the apparent femoral secretion rates of the angjotensins in the nephrectomized group. Low plasma levels of Ang I and Ang II remained in the nephrectomized group, representing some locally generated angjotensins. These results indicate that isoproterenol, by acting on βadrenergic receptors, caused an increase of systemic and local angiotensin production, which depends on the presence of the kidney.