THE EFFECT OF HYPERTENSIVE EPISODES AND CARDIAC HYPERTROPHY ON THE CANINE CARDIAC BAROREFLEX

1. Left ventricular (LV) hypertrophy has been implicated in the reduction of baroreflex sensitivity present in hypertension. The aim of the current study was to investigate the mean arterial pressure-heart rate reflex (MAP-HR) in a model which induced left ventricular hypertrophy but no sustained blood pressure elevation. 2. Five mongrel dogs were exposed to transient blood pressure elevation of between 20 and 30 mmHg, through hindlimb compression using a pneumatic pressure suit, for 7 h per day, 6 days per week for 6 weeks. Resting blood pressure was not altered by the 6 week hindlimb compression intervention. 3. Echocardiographically determined LV mass (mean ± s.e.m.) was 116.0 ± 7.4 g prior to hindlimb compression (baseline) and elevated to 125.4 ± 8.1 g (P= 0.003) after 6 weeks of compression. A reduction in the early (E) to late (A) transmitral diastolic flow ratio (E/A) from 1.80 ± 0.06 at baseline to 1.54 ± 0.09 (P = 0.037) after the 6 week intervention suggested that cardiac compliance was reduced. 4. The maximum gain of the MAP-HR reflex, studied using the ‘steady-state’ drug technique, when blood pressure was normal, showed a trend for reduction from 3.85 ± 0.43 beats/min per mmHg at baseline to 3.10 ± 0.45 beats/min per mmHg (P= 0.067) after 6 weeks of compression. This gain reduction became significant after β-adrenoceptor blockade with propranolol (3.13 ± 0.55 vs 2.32 ± 0.25 beats/min per mmHg; P= 0.039). Covariant analysis showed a significant inverse correlation between LV mass and maximum gain (r= 0.96; P<0.001) during the 6 week compression period. 5. The MAP-HR reflex changes in this model mimic those present in hypertension and implicate cardiac hypertrophy as one possible mediator.     

Ocular Pharmacokinetics and Pharmacodynamics of Phenylephrine and Phenylephrine Oxazolidine in Rabbit Eyes

The aqueous humor concentration of phenylephrine and its corresponding mydriatic response were measured over time in New Zealand albino rabbit eyes following a 10-µl topical instillation of a phenylephrine HC1 viscous solution (10%) or a phenylephrine oxazolidine (prodrug) suspension in sesame oil (1 and 10%). The bioavailability of a 1% prodrug suspension in the rabbit eye (AUC of aqueous humor concentration vs time) was 30% lower than that of a 10% phenylephrine solution (P < 0.1) with the exception that the peak time occurred 34 min earlier with the prodrug. A 10% prodrug suspension increased the aqueous humor bioavailability approximately eightfold but improved the mydriatic activity (AUC of mydriasis vs time) only fourfold. The pharmacokinetic parameters, apparent absorption, and elimination rate constants, of phenylephrine and the prodrug were determined from aqueous humor concentration–time and mydriasis–time profiles. The study showed that the kinetic parameters of phenylephrine estimated from its mydriasis profile do not accurately reflect the kinetics of drug distribution in the iris. These parameters also varied with the instillation of phenylephrine solution or prodrug suspensions. A mydriatic tolerance of the pupil response was apparent after the topical instillation of phenylephrine solution. The mydriatic tolerance may be due to the decrease in receptor number in the iris dilator muscle.     

Intravenous Phenylephrine Preconditioning of Cardiac Grafts From Non–Heart-Beating Donors

Background. Hypoxia and warm ischemia produce severe injury to cardiac grafts harvested from non-heart-beating donors. To potentially improve recovery of such grafts, we studied the effects of intravenous phenylephrine preconditioning.

Methods. Thirty-seven blood-perfused rabbit hearts were studied. Three groups of non-heart-beating donors underwent intravenous treatment with phenylephrine at 12.5 (n = 8), 25 (n = 7), or 50 μg/kg (n = 7) before initiation of apnea. Non-heart-beating controls (n = 8) received saline vehicle. Hypoxic cardiac arrest occurred after 6 to 12 minutes of apnea, followed by 20 minutes of warm in vivo ischemia. A 45-minute period of ex vivo reperfusion ensued. Nonischemic controls (n = 7) were perfused without antecedent hypoxia or ischemia.

Results. Phenylephrine 25 μg/kg significantly delayed the onset of hypoxic cardiac arrest compared with saline controls (9.6 ± 0.5 versus 7.7 ± 0.4 minutes; p = 0.00001), yet improved recovery of left ventricular developed pressure compared with saline controls (57.1 ± 5.3 versus 41.0 ± 3.4 mm Hg; p = 0.04). Phenylephrine 25 μg/kg also yielded a trend toward less myocardial edema than saline vehicle (p = 0.09).

Conclusions. Functional recovery of nonbeating cardiac grafts is improved by preconditioning. We provide evidence that the myocardium can be preconditioned with phenylephrine against hypoxic cardiac arrest.     

不同浓度滴量的新福林眼液对治疗指数的影响

目的探索如何提高新福林滴眼液的治疗指数。方法我们用１０％－４０μｌ、１０％－１０μｌ、２．５％－４０μｌ、２．５％－１０μｌ４组新福林滴眼液给１６名健康大学生分次进行扩瞳试验，观察它们的扩瞳效果及用药后心率、血压的变化。结果同一容量１０％比２．５％新福林扩瞳效果强。同一浓度１０μｌ与４０μｌ新福林扩瞳效果相似。１０％－１０μｌ与２．５％－４０μｌ其新福林含量相等，但前者扩瞳效果要优于后者。４组新福林眼液对实验对象的心率和血压均无显著影响。结论采用高浓度小滴量新福林眼液扩瞳，不仅可以减少滴眼液的用量，提高其生物可用度，更重要的是可使其治疗指数得以显著提高。     

Intravenous Phenylephrine Preconditioning of Cardiac Grafts From Non–Heart-Beating Donors

Background. Hypoxia and warm ischemia produce severe injury to cardiac grafts harvested from non–heart-beating donors. To potentially improve recovery of such grafts, we studied the effects of intravenous phenylephrine preconditioning.Methods. Thirty-seven blood-perfused rabbit hearts were studied. Three groups of non–heart-beating donors underwent intravenous treatment with phenylephrine at 12.5 (n = 8), 25 (n = 7), or 50 μg/kg (n = 7) before initiation of apnea. Non–heart-beating controls (n = 8) received saline vehicle. Hypoxic cardiac arrest occurred after 6 to 12 minutes of apnea, followed by 20 minutes of warm in vivo ischemia. A 45-minute period of ex vivo reperfusion ensued. Nonischemic controls (n = 7) were perfused without antecedent hypoxia or ischemia.Results. Phenylephrine 25 μg/kg significantly delayed the onset of hypoxic cardiac arrest compared with saline controls (9.6 ± 0.5 versus 7.7 ± 0.4 minutes; p = 0.00001), yet improved recovery of left ventricular developed pressure compared with saline controls (57.1 ± 5.3 versus 41.0 ± 3.4 mm Hg; p = 0.04). Phenylephrine 25 μg/kg also yielded a trend toward less myocardial edema than saline vehicle (p = 0.09).Conclusions. Functional recovery of nonbeating cardiac grafts is improved by preconditioning. We provide evidence that the myocardium can be preconditioned with phenylephrine against hypoxic cardiac arrest.(Ann Thorac Surg 1997;63:1664–8)     

Discharge activity of single muscle vasoconstrictor efferents in cats during opposite changes in arterial pressure

Signals of individual muscle vasoconstrictor efferents of gastrocnemius muscle were recorded in narcotized cat during rise and fall of systemic arterial pressure induced by phenylephrine and sodium nitroprusside, respectively. In control, mean discharge rate of these efferents was 2.0±0.4 Hz. Phenylephrine (45 g/kg) increased arterial pressure from 120.3±4.2 to 170.7±8.2 mm Hg. This increase was accompanied by a short-term (5-10 sec) decrease in discharge rate of muscle vasoconstrictor efferents to 0.5±0.3 Hz followed by virtually complete recovery of muscle discharge rate against the background of increased arterial pressure. Sodium nitroprusside (30 g/kg) decreased arterial pressure from 132.8±6.2 to 64.1±4.3 mm Hg. Under these conditions the discharge rate of vasoconstrictor efferents increased to 3.5±0.6 Hz and remained at this level throughout the hypotension period (2-3 min). Unloading of baroreceptors (occlusion of the carotid artery) increased the discharge rate of muscle vasoconstrictor efferents throughout the occlusion period (up to 30 sec). Thus, blood pressure rise and drop induced asymmetric by their duration changes in the discharge responses of muscle vasoconstrictor efferents. Phenylephrine increased asymmetry of the vasoconstrictor component of the baroreflex and induced cumulative rise of discharge rate of muscle vasoconstrictor efferents in response to a series of short-term reversible blood pressure jumps caused by repeated occlusions of the abdominal aorta. Our findings extend our knowledge on the efferent component of the baroreflex regulation and on possible mechanisms of hypertension.     

Differential actions of exogenous and intracellular spermine on contractile activity in smooth muscle of rat portal vein

Effects of the naturally occurring polyamine spermine on electrical and contractile properties of the rat portal vein were studied. 1 mM spermine nearly abolished spike activity and spontaneous contractions and decreased the intracellular Ca²⁺ concentration ([Ca²⁺],). The phasic force responses to 0.1 and 1 μM phenylephrine were partially inhibited, but not the sustain plateau contraction caused by 5 /IM phenylephrine. The Ca²⁺-force relation in high-K⁺ (128 mM)-depolarized veins was shifted to the right, EC₅₀ for Ca²⁺ increasing from 0.50 ± 0.03 mM (control, n= 8) to 0.65 ± 0.06 and to 0.94 ± 0.03 at 1 (n – 4) and 10 (n = 3) mM spermine, respectively. However, at a Ca²⁺ concentration of 2.5 mM, giving maximal force, there was no effect of spermine (1 mM) on either force or [Ca²⁺],. Whereas extracellular spermine thus reduced contractile activity at moderate levels of stimulation, increased intracellular concentration of spermine potentiated the force response to Ca²⁺. Intracellular loading of spermine by reversible permeabilization increased its concentration by 2–3 times. The spontaneous activity and response to phenylephrine were unchanged. However, the Ca²⁺-force relation of depolarized veins was shifted to the left, EC₅₀ decreasing from 0.51 ± 0.04 mM in controls (n= 7) to 0.36 ± 0.02 mM in the loaded veins (n= 9). Spermine increased Ca²⁺-activated force in portal veins permeabilized with β-escin. The degree of potentiation was consistent with observed effects in spermine-loaded intact veins. The results suggest that spermine at physiological intracellular concentration may contribute to the determination of Ca²⁺ sensitivity in vascular smooth muscle cells.